Patent Publication Number: US-11034751-B1

Title: Methods and compositions for treating cancer using serotonin receptor inhibitors

Description:
CROSS-REFERENCE 
     This application claims the benefit of U.S. Provisional Application No. 62/623,665, filed Jan. 31, 2018, which is incorporated herein in its entirety by reference. 
    
    
     BACKGROUND 
     Cancer is still one of the deadliest threats to human health. In 2012, there were 14 million new cases of cancer worldwide and 8.2 million cancer-related deaths. The number of new cancer cases is expected to rise to 22 million by 2030, and worldwide cancer deaths are projected to increase by 60%. Thus, there remains a need in the field for treatments for cancer. 
     SUMMARY OF THE INVENTION 
     The present invention provides methods for treating cancer using serotonin receptor inhibitors, such as serotonin receptor inhibitory antibodies, among others. The invention also features compositions containing serotonin receptor inhibitors, methods of diagnosing patients with serotonin receptor-associated cancer, and methods of predicting the response of cancer in a subject to treatment with serotonin receptor inhibitors, such as HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7 inhibitors. 
     In a first aspect, the invention provides a method of treating a subject with cancer, by administering to the subject an effective amount of a serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of treating a subject with cancer by contacting an immune cell, tumor, tumor microenvironment, site of metastasis, lymph node, spleen, secondary lymphoid organ, or tertiary lymphoid organ with an effective amount of a serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of treating a subject identified as having cancer by administering to the subject an effective amount of a serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of treating a subject identified as having cancer by contacting an immune cell, tumor, tumor microenvironment, site of metastasis, lymph node, spleen, secondary lymphoid organ, or tertiary lymphoid organ with an effective amount of a serotonin receptor inhibitor. 
     In some embodiments of any of the above aspects, the cancer is serotonin receptor-associated cancer (e.g., a cancer associated with an immune cell that expresses one or more serotonin receptor listed in Table 1, e.g., one or more of HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7, such as HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7-associated cancer). 
     In another aspect, the invention provides a method of increasing levels of one or more pro-inflammatory cytokine in a subject in need thereof by administering to the subject an effective amount of a serotonin receptor inhibitor. In some embodiments, the subject is a subject with serotonin receptor-associated cancer. In some embodiments, the one or more pro-inflammatory cytokine includes interleukin-8 (IL-8). In some embodiments, the method further includes determining the level of one or more pro-inflammatory cytokine after administration of the serotonin receptor inhibitor. In another aspect, the invention provides a method of treating a subject with cancer by: a) identifying a subject with serotonin receptor-associated cancer; and b) administering to the subject an effective amount of a serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of treating a subject with cancer by: a) identifying a subject with serotonin receptor-associated cancer; and b) contacting an immune cell, tumor, tumor microenvironment, site of metastasis, lymph node, spleen, secondary lymphoid organ, or tertiary lymphoid organ with an effective amount of a serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of treating a subject with serotonin receptor-associated cancer by administering to the subject an effective amount of a serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of treating a subject with serotonin receptor-associated cancer by contacting an immune cell, tumor, tumor microenvironment, site of metastasis, lymph node, spleen, secondary lymphoid organ, or tertiary lymphoid organ with an effective amount of a serotonin receptor inhibitor. 
     In some embodiments of any of the above aspects, the method includes contacting an immune cell with an effective amount of a serotonin receptor inhibitor. In some embodiments of any of the above aspects, the method includes contacting a tumor with an effective amount of a serotonin receptor inhibitor. In some embodiments of any of the above aspects, the method includes contacting a tumor microenvironment with an effective amount of a serotonin receptor inhibitor. In some embodiments of any of the above aspects, the method includes contacting a site of metastasis with an effective amount of a serotonin receptor inhibitor. In some embodiments of any of the above aspects, the method includes contacting a lymph node with an effective amount of a serotonin receptor inhibitor. In some embodiments of any of the above aspects, the method includes contacting a spleen with an effective amount of a serotonin receptor inhibitor. In some embodiments of any of the above aspects, the method includes contacting a secondary lymphoid organ with an effective amount of a serotonin receptor inhibitor. In some embodiments of any of the above aspects, the method includes contacting a tertiary lymphoid organ with an effective amount of a serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of increasing macrophage production of one or more pro-inflammatory cytokine by contacting a macrophage with an effective amount of a serotonin receptor inhibitor. In some embodiments, the macrophage is a macrophage expressing one or more serotonin receptors (e.g., one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7). In some embodiments, the one or more pro-inflammatory cytokine includes IL-8. 
     In some embodiments of any of the above aspects, the serotonin receptor-associated cancer is associated with expression of one or more serotonin receptors in an immune cell (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7, e.g., serotonin receptor expression in an immune cell, e.g., a T cell, macrophage, monocyte, or myeloid-derived suppressor cell). In some embodiments of any of the above aspects, the serotonin receptor-associated cancer is associated with overexpression of one or more serotonin receptors in an immune cell (e.g., overexpression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7, e.g., serotonin receptor overexpression in an immune cell, e.g., a T cell, macrophage, monocyte, or myeloid-derived suppressor cell). In some embodiments of any of the above aspects, the serotonin receptor-associated cancer is infiltrated with immune cells (e.g., T cells, macrophages, monocytes, or myeloid-derived suppressor cells) that express or overexpress one or more serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7). In some embodiments of any of the above aspects, the method includes increasing the development of high endothelial venules (HEVs) or tertiary lymphoid organs (TLOs). In some embodiments of any of the above aspects, the method includes increasing an immune cell activity. In some embodiments of any of the above aspects, the method includes decreasing an immune cell activity. 
     In another aspect, the invention provides a method of increasing an immune cell activity in a subject in need thereof by contacting an immune cell with an effective amount of a serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of increasing an immune cell activity in a subject in need thereof by administering to a subject an effective amount of a serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of decreasing an immune cell activity in a subject in need thereof by contacting an immune cell with an effective amount of a serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of decreasing an immune cell activity in a subject in need thereof by administering to a subject an effective amount of a serotonin receptor inhibitor. 
     In some embodiments of any of the above aspects, the immune cell activity that is increased is immune cell migration, polarization (e.g., polarization toward an inflammatory state), proliferation, recruitment, differentiation, tumor homing, activation, cytokine production (e.g., pro-inflammatory cytokine production), degranulation, maturation, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), or antigen presentation. 
     In some embodiments of any of the above aspects, the immune cell activity that is decreased is immune cell tumor egress and/or serotonin receptor expression (e.g., gene or protein expression). 
     In another aspect, the invention provides a method of treating a subject with an immune cell-infiltrated tumor by administering to the subject an effective amount of a serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of treating a subject with an immune cell-infiltrated tumor by contacting the tumor with an effective amount of a serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of treating a subject with an immune cell-infiltrated tumor by contacting an immune cell in the tumor with an effective amount of a serotonin receptor inhibitor. 
     In some embodiments of any of the above aspects, the immune cell is a T cell, a monocyte, a macrophage, an M2 macrophage, or a myeloid-derived suppressor cell (MDSC). In some embodiments of any of the above aspects, the immune cell expresses one or more serotonin receptors (e.g., one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7). 
     In some embodiments of any of the above aspects, the method further includes contacting an immune cell isolated from the subject with a serotonin receptor inhibitor and evaluating the response of the immune cell prior to administration of the serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of treating a subject with cancer, the method including the steps of a) contacting an immune cell isolated from the subject with an serotonin receptor inhibitor and evaluating a response of the immune cell; and b) administering to the subject an effective amount of a serotonin receptor inhibitor if the response of the immune cell is modulated by the serotonin receptor inhibitor (e.g., if the serotonin receptor inhibitor increases migration, polarization (e.g., polarization toward an inflammatory state), proliferation, recruitment, differentiation, tumor homing, activation, cytokine production (e.g., pro-inflammatory cytokine production, e.g., IL-8 production), degranulation, maturation, ADCC, ADCP, and/or antigen presentation). 
     In another aspect, the invention provides a method of treating a subject with cancer, the method including the steps of a) contacting an immune cell isolated from the subject with a serotonin receptor inhibitor and evaluating a response of the immune cell; and b) contacting an immune cell, a tumor, a tumor microenvironment, a site of metastasis, a lymph node, a spleen, a secondary lymphoid organ, or a tertiary lymphoid organ with an effective amount of a serotonin receptor inhibitor if the response of the immune cell is modulated by the serotonin receptor inhibitor (e.g., if the serotonin receptor inhibitor increases migration, polarization (e.g., polarization toward an inflammatory state), proliferation, recruitment, differentiation, tumor homing, activation, cytokine production (e.g., pro-inflammatory cytokine production, e.g., IL-8 production), degranulation, maturation, ADCC, ADCP, and/or antigen presentation). 
     In another aspect, the invention provides a method of treating a subject with cancer, the method including the steps of a) contacting an immune cell or isolated from the subject with a serotonin receptor inhibitor and evaluating a response of the immune cell; and b) administering to the subject an effective amount of a serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of predicting the response of a cancer in a subject to treatment with a serotonin receptor inhibitor by contacting an immune cell isolated from the subject with a serotonin receptor inhibitor and evaluating the response of the immune cell. 
     In another aspect, the invention provides a method of predicting the response of a cancer in a subject to treatment with a serotonin receptor inhibitor by contacting an immune cell-infiltrated tumor biopsy isolated from the subject with a serotonin receptor inhibitor and evaluating the response of the immune cell. 
     In some embodiments of any of the above aspects, the evaluating includes assessing cancer cell growth, cancer cell proliferation, cancer cell metastasis, cancer cell migration, cancer cell invasion, cancer cell death, cancer cell autophagy, immune cell migration, immune cell proliferation, immune cell recruitment, immune cell tumor homing, immune cell tumor egress, immune cell differentiation, immune cell activation, immune cell polarization, immune cell cytokine production, immune cell degranulation, immune cell maturation, immune cell ADCC, immune cell ADCP, immune cell antigen presentation, or immune cell serotonin receptor expression (e.g., expression of a serotonin receptor listed in Table 1, e.g., expression of one or more of HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7). 
     In another aspect, the invention provides a method of predicting the response of a cancer in a subject to treatment with a serotonin receptor inhibitor by: a) isolating an immune cell from the subject; b) measuring the expression of one or more serotonin receptors (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7 expression) in the immune cell; and c) comparing serotonin receptor expression in the immune cell to a reference, wherein increased expression of one or more serotonin receptors in the immune cell as compared to the reference indicates that the subject will respond to treatment with a serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of determining if an immune cell expresses a functional serotonin receptor by contacting an isolated immune cell with a serotonin receptor antagonist and evaluating pro-inflammatory cytokine production (e.g., IL-8 secretion). In some embodiments, an increase in pro-inflammatory cytokine production (e.g., IL-8 production) indicates that the immune cell expresses a functional serotonin receptor. 
     In some embodiments of any of the above aspects, the method further includes contacting the immune cell with a serotonin receptor inhibitor. 
     In another aspect, the invention provides a method of characterizing a cancer in a subject by: a) isolating an immune cell from the subject; b) measuring the expression of one or more serotonin receptors (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7 expression) in the immune cell; and c) comparing serotonin receptor expression in the immune cell to a reference, wherein increased expression of one or more serotonin receptors in the immune cell as compared to the reference indicates that the subject has serotonin receptor-associated cancer. 
     In another aspect, the invention provides a method of identifying a subject as having serotonin receptor-associated cancer by: a) isolating an immune cell from the subject; b) measuring the expression of one or more serotonin receptors (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7 expression) in the immune cell; and c) comparing serotonin receptor expression in the immune cell to a reference, wherein increased expression of one or more serotonin receptors in the immune cell as compared to the reference indicates that the subject has serotonin receptor-associated cancer. 
     In some embodiments of any of the above aspects, the method further includes providing a serotonin receptor inhibitor suitable for administration to the subject. In some embodiments of any of the above aspects, the method further includes administering to the subject an effective amount of a serotonin receptor inhibitor. 
     In some embodiments of any the above aspects, the serotonin receptor inhibitor is a serotonin receptor-specific inhibitor (e.g., an HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7-specific inhibitor). 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor is a serotonin receptor function blocker. 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor is a serotonin receptor signaling inhibitor. 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor is a neurotransmission blocker. In some embodiments, the neurotransmission blocker is a neurotoxin (e.g., a neurotoxin listed in Table 13). In some embodiments, the neurotoxin is trichothecene mycotoxin deoxynivalenol (DON) or pertussis toxin. 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor reduces serotonin receptor expression or activity. 
     In some embodiments of any of the above aspects, the cancer is a solid tumor, an immune cell-infiltrated tumor or cancer (e.g., a tumor or cancer that is infiltrated by T cells, macrophages, monocytes, M2 macrophages, or MDSCs), a cancer that is treated with immunotherapy (e.g., melanoma, non-small cell lung cancer, kidney cancer, renal cell carcinoma, bladder cancer, head and neck cancer, Hodgkin&#39;s lymphoma, leukemia, urothelial carcinoma, gastric cancer, microsatellite instability-high cancer, colorectal cancer, or hepatocellular carcinoma), or a cancer for which immunotherapy is not effective (e.g., a cancer that does not respond to immunotherapy or a cancer that did not respond to prior treatment with immunotherapy). 
     In some embodiments of any of the above aspects, the cancer is serotonin receptor-associated cancer. 
     In some embodiments of any of the above aspects, the immune cell-infiltrated tumor or cancer is a hot tumor (e.g., a tumor that that contains T cells and expresses neoantigens). In some embodiments, the hot tumor is a bladder cancer, head and neck cancer, kidney cancer, liver cancer, melanoma, non-small cell lung cancer, or microsatellite instability high cancer. In some embodiments of any of the above aspects, the immune cell-infiltrated tumor or cancer is a cold tumor (e.g., a tumor or cancer associated with suppressive immune cells, such as myeloid-derived suppressor cells and/or Tregs). In some embodiments, the cold tumor or cancer is a cancer or tumor that does not respond to immunotherapy. In some embodiments, the cold tumor or cancer is ovarian cancer, prostate cancer, or pancreatic cancer. In some embodiments of any of the above aspects, the tumor or cancer in the subject is identified as an immune cell-infiltrated tumor or cancer by evaluating a tumor or cancer sample isolated from the subject (e.g., a biopsy) for expression of an immune cell marker (e.g., one or more a markers listed in Table 4). 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor is administered locally. In some embodiments of any of the above aspects, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor is administered intratumorally, into a lymphoid organ, into a site of metastasis, into a tumor microenvironment, into a lymph node, or into the spleen. In some embodiments, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor is administered intratumorally. In some embodiments, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor is administered to a tumor microenvironment. In some embodiments, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor is administered to a site of metastasis. In some embodiments, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor is administered to a lymph node. In some embodiments, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor is administered to a lymphoid organ. In some embodiments, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor is administered to the spleen. In some embodiments, the lymphoid organ is a secondary or tertiary lymphoid organ. In some embodiments of any of the above aspects, the method further includes administering a second therapeutic agent. 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor decreases tumor volume, decreases tumor growth, decreases tumor innervation, decreases cancer cell proliferation, decreases cancer cell invasion, decreases cancer cell migration, decreases cancer cell metastasis, increases cancer cell death, increases cancer cell autophagy, increases time to recurrence, improves survival, increases the development of HEVs or TLOs, increases immune cell migration, increases immune cell proliferation, increases immune cell recruitment, increases immune cell tumor homing, decreases immune cell tumor egress, increases immune cell differentiation, increases immune cell activation, increases immune cell polarization, increases immune cell cytokine production, increases immune cell degranulation, increases immune cell maturation, increases immune cell ADCC, increases immune cell ADCP, increases immune cell antigen presentation, or decreases immune cell serotonin receptor expression (e.g., gene or protein expression of a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7expression). 
     In some embodiments of any of the above aspects, the method further includes measuring one or more of tumor volume, tumor growth, tumor innervation, cancer cell proliferation, cancer cell invasion, cancer cell migration, cancer cell metastasis, cancer cell death, cancer cell autophagy, the development of HEVs or TLOs, immune cell migration, immune cell proliferation, immune cell recruitment, immune cell tumor homing, immune cell tumor egress, immune cell differentiation, immune cell activation, immune cell polarization, immune cell cytokine production, immune cell degranulation, immune cell maturation, immune cell ADCC, immune cell ADCP, immune cell antigen presentation, or immune cell serotonin receptor expression (e.g., expression of a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7 expression) before administration of the serotonin receptor inhibitor or serotonin receptor-specific inhibitor. 
     In some embodiments of any of the above aspects, the method further includes measuring one or more of tumor volume, tumor growth, tumor innervation, cancer cell proliferation, cancer cell invasion, cancer cell migration, cancer cell metastasis, cancer cell death, cancer cell autophagy, the development of HEVs or TLOs, immune cell migration, immune cell proliferation, immune cell recruitment, immune cell tumor homing, immune cell tumor egress, immune cell differentiation, immune cell activation, immune cell polarization, immune cell cytokine production, immune cell degranulation, immune cell maturation, immune cell ADCC, immune cell ADCP, immune cell antigen presentation, or immune cell serotonin receptor expression (e.g., expression of a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7 expression) after administration of the serotonin receptor inhibitor or serotonin receptor-specific inhibitor. 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor is administered in an amount sufficient to treat the cancer or tumor, cause remission, decrease tumor volume, decrease tumor growth, decrease tumor innervation, decrease cancer cell proliferation, decrease cancer cell invasion, decrease cancer cell migration, decrease cancer cell metastasis, increase cancer cell death, increase cancer cell autophagy, increase time to recurrence, improve survival, increase the development of HEVs or TLOs, increase immune cell migration, increase immune cell proliferation, increase immune cell recruitment, increase immune cell tumor homing, decrease immune cell tumor egress, increase immune cell differentiation, increase immune cell activation, increase immune cell polarization, increase immune cell cytokine production, increase immune cell degranulation, increase immune cell maturation, increase immune cell ADCC, increase immune cell ADCP, increase immune cell antigen presentation, or decrease immune cell serotonin receptor expression (e.g., expression of a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7expression). 
     In some embodiments of any of the above aspects, the method further includes monitoring tumor or cancer progression (e.g., monitoring one or more of tumor volume, tumor or cancer cell growth, tumor innervation, tumor number, cancer cell proliferation, cancer cell invasion, cancer cell metastasis, cancer cell death, cancer cell autophagy, the development of HEVs or TLOs, immune cell migration, immune cell proliferation, immune cell recruitment, immune cell lymph node homing, immune cell lymph node egress, immune cell tumor homing, immune cell tumor egress, immune cell differentiation, immune cell activation, immune cell polarization, immune cell cytokine production, immune cell degranulation, immune cell maturation, immune cell ADCC, immune cell ADCP, immune cell antigen presentation, inflammation, or immune cell mGluR8 expression) of after administration of the serotonin receptor inhibitor or serotonin receptor-specific inhibitor. 
     In some embodiments of any of the above aspects, the subject is not diagnosed as having a neuropsychiatric disorder, sleep apnea, nausea, or migraine headaches. 
     In some embodiments of any of the above aspects, the cytokine is IL-8. 
     In some embodiments of any of the above aspects, increased IL-8 production increases neutrophil recruitment, tumor homing, and/or activation. 
     In some embodiments of any of the above aspects, the subject is a human. 
     In another aspect, the invention provides an anti-cancer therapy containing a serotonin receptor inhibitor and a second agent selected from the group consisting of checkpoint inhibitors, chemotherapeutic agents, biologic cancer agents (e.g., an agent listed in Table 7), cancer-specific agents (e.g., an agent listed in Table 8), anti-angiogenic drugs, drugs that target cancer metabolism, antibodies that mark a cancer cell surface for destruction, antibody-drug conjugates, cell therapies, commonly used anti-neoplastic agents, non-drug therapies, CAR-T therapy, neurotransmission modulators, and neuronal growth factor modulators. 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor is a serotonin receptor inhibitory antibody or an antigen binding fragment thereof. In some embodiments of any of the above aspects, the serotonin receptor inhibitory antibody is a serotonin receptor-specific inhibitory antibody or an antigen binding fragment thereof (e.g., an HTR1F-specific inhibitory antibody, an HTR2B-specific inhibitory antibody, an HRT2C-specific inhibitory antibody, an HTR3A specific-inhibitory antibody, an HTR6 specific-inhibitory antibody, or an HTR7-specific inhibitory antibody). 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor is a small molecule inhibitor (e.g., antagonist) listed in Table 2. 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor is a neurotoxin (e.g., a neurotoxin listed in Table 13, trichothecene mycotoxin deoxynivalenol (DON), or pertussis toxin). In some embodiments of any of the above aspects, the serotonin receptor inhibitor is a serotonin receptor function blocker. 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor is a serotonin receptor signaling inhibitor. In some embodiments of any of the above aspects, the serotonin receptor signaling inhibitor is a small molecule listed in Table 3. In another aspect, the invention provides a pharmaceutical composition including a serotonin receptor inhibitor. 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor is a serotonin receptor inhibitory antibody or an antigen binding fragment thereof. In some embodiments of any of the above aspects, the serotonin receptor inhibitory antibody is a serotonin receptor-specific inhibitory antibody or an antigen binding fragment thereof (e.g., an HTR1F-specific inhibitory antibody, an HTR2B-specific inhibitory antibody, an HRT2C-specific inhibitory antibody, an HTR3A specific-inhibitory antibody, an HTR6 specific-inhibitory antibody, or an HTR7-specific inhibitory antibody). 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor is a small molecule inhibitor (e.g., antagonist) listed in Table 2. 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor is a neurotoxin (e.g., a neurotoxin listed in Table 13, DON or pertussis toxin). 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor is an inhibitory RNA (e.g., small interfering RNA (siRNA), short hairpin RNA (shRNA), or microRNA (miRNA)) directed to a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor is nuclease (e.g., transcription activator-like effector nuclease (TALEN), zinc finger nuclease (ZFN), or CRISPR associated protein (Cas), e.g., Cas9) directed to a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitory antibody exhibits one or more of the following activities: (a) induces antibody-dependent cell killing of a serotonin receptor-expressing cell; (b) induces antibody-dependent cell killing of a serotonin receptor-expressing cell; (c) induces phagocytosis of a serotonin receptor-expressing cell; (d) induces opsonization of a serotonin receptor-expressing cell; (e) induces downregulation of a serotonin receptor; (f) prevents dimerization of a serotonin receptor; (g) does not have agonistic activity; (h) binds to one or more extracellular regions of a serotonin receptor; or (i) antagonizes a serotonin receptor. In some embodiments of any of the above aspects, the serotonin receptor inhibitory antibody is an HTR1F-specific inhibitory antibody and the antibody binds to or blocks an extracellular domain of HTR1F (amino acids 1-29, 84-97, 162-178, 312-329) or amino acids 99-108 and/or 306-310 of HTR1F. In some embodiments of any of the above aspects, the serotonin receptor inhibitory antibody is an HTR2B-specific inhibitory antibody and the antibody binds to or blocks one or more of residues D135, V136, S139, T140, K211, F217, W337, F340, N344, or Y370 of HTR2B. In some embodiments of any of the above aspects, the serotonin receptor inhibitory antibody is an HTR2C-specific inhibitory antibody and the antibody binds to or blocks one or more of residues P159, S456, or V458 on HTR2C. In some embodiments of any of the above aspects, the serotonin receptor inhibitory antibody is an HTR3A-specific inhibitory antibody and the antibody binds to or blocks an extracellular domain of HTR3A (amino acids 24-241, 293-302, 476-478), amino acids 178, 432, 436, and/or 440 of HTR3A, or the expansion of amino acid 306(G) in the 5HTR3-AL isoform. In some embodiments of any of the above aspects, the serotonin receptor inhibitory antibody is an HTR6-specific inhibitory antibody and the antibody binds to or blocks an extracellular domain of HTR6 (amino acids 1-34, 86-100, 168-184, and/or 291-295). In some embodiments of any of the above aspects, the serotonin receptor inhibitory antibody is an HTR7-specific inhibitory antibody and the antibody binds to or blocks one or more of sites 5, 66, or 401 of HTR7. 
     In some embodiments of the above aspects, the composition further includes a second therapeutic agent. 
     In some embodiments of any of the above aspects, the composition further includes a pharmaceutically acceptable excipient. 
     In some embodiments of any of the above aspects, the second therapeutic agent is an anti-cancer therapeutic, a serotonin receptor signaling inhibitor, a serotonin receptor function blocker, a neurotransmission modulator, or a neuronal growth factor modulator. 
     In some embodiments of any of the above aspects, the anti-cancer therapeutic is a checkpoint inhibitor, a chemotherapeutic agent, a biologic cancer agent (e.g., an agent listed in Table 7), a cancer-specific agent (e.g., an agent listed in Table 8), an anti-angiogenic drug, a drug that targets cancer metabolism, an antibody that marks a cancer cell surface for destruction, an antibody-drug conjugate, a cell therapy, a commonly used anti-neoplastic agent, CAR-T therapy, or a non-drug therapy. 
     In some embodiments of any of the above aspects, the checkpoint inhibitor is an inhibitory antibody, a fusion protein, an agent that interacts with a checkpoint protein, an agent that interacts with the ligand of a checkpoint protein, an inhibitor of CTLA-4, an inhibitor of PD-1, an inhibitor of PDL1, an inhibitor of PDL2, or an inhibitor of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAGS, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, or B-7 family ligands. 
     In some embodiments of any of the above aspects, the neurotransmission modulator is neurotoxin listed in Table 13, or a modulator (e.g., agonist or antagonist) of a neurotransmitter receptor listed in Table 9 or a neurotransmitter listed in Table 10. In some embodiments, the modulator of a neurotransmitter receptor listed in Table 9 or a neurotransmitter listed in Table 10 is an agonist or antagonist listed in Tables 11A-11J or a modulator listed in Table 12. 
     In some embodiments of any of the above aspects, the neuronal growth factor modulator is an agonist or antagonist of a neuronal growth factor listed in Table 10. In some embodiments, the modulator of a neuronal growth factor listed in Table 14 is an antibody listed in Table 15 or an agonist or antagonist listed in Table 16. In some embodiments, the modulator of a neuronal growth factor listed in Table 14 is selected from the group consisting of etanercept, thalidomide, lenalidomide, pomalidomide, pentoxifylline, bupropion, DOI, disitertide, and trabedersen. 
     In some embodiments of any of the above aspects, the biologic cancer agent is an antibody listed in Table 7. 
     In some embodiments of any of the above aspects, the cancer is a cancer listed in column 1 of Table 8 and the second agent is a corresponding anti-cancer agent listed in column 2 of Table 8. 
     In some embodiments of any of the above aspects, the serotonin receptor function blocker is a serotonin receptor-specific inhibitor, such as an HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7 specific inhibitor (e.g., a serotonin receptor-specific inhibitory antibody, a serotonin receptor-selective small molecule inhibitor (e.g., antagonist), or an inhibitory RNA or nuclease directed to a serotonin receptor). In some embodiments of any of the above aspects, the serotonin receptor function blocker is a serotonin receptor inhibitory antibody or an antigen binding fragment thereof. In some embodiments of any of the above aspects, the serotonin receptor inhibitory antibody is a serotonin receptor-specific inhibitory antibody or an antigen binding fragment thereof (e.g., an HTR1F-specific inhibitory antibody, an HTR2B-specific inhibitory antibody, an HRT2C-specific inhibitory antibody, an HTR3A specific-inhibitory antibody, an HTR6 specific-inhibitory antibody, or an HTR7-specific inhibitory antibody). In some embodiments of any of the above aspects, the serotonin receptor function blocker is a small molecule serotonin receptor inhibitor (e.g., antagonist) listed in Table 2. In some embodiments of any of the above aspects, the serotonin receptor function blocker is an inhibitory RNA directed to a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR2B, HTR2C, or HTR7). In some embodiments of any of the above aspects, the serotonin receptor function blocker is a nuclease (e.g., a TALEN, ZFN, or Cas, e.g., Cas9) directed to a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). In some embodiments of any of the above aspects, the serotonin receptor function blocker is a neurotransmission blocker. In some embodiments, the neurotransmission blocker is a neurotoxin listed in Table 13, DON, or pertussis toxin. 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor is selected from the group consisting of an antibody, a small molecule, an RNA molecule, a nuclease, and a viral vector. In some embodiments, the antibody is a serotonin receptor inhibitory antibody or an antigen binding fragment thereof. In some embodiments, the serotonin receptor inhibitory antibody is a serotonin receptor-specific inhibitory antibody or an antigen binding fragment thereof (e.g., an HTR1F-specific inhibitory antibody, an HTR2B-specific inhibitory antibody, an HRT2C-specific inhibitory antibody, an HTR3A specific-inhibitory antibody, an HTR6 specific-inhibitory antibody, or an HTR7-specific inhibitory antibody). In some embodiments, the small molecule is a small molecule listed in Table 2 or Table 3. In some embodiments, the viral vector expresses a neurotoxin listed in Table 13, DON, or pertussis toxin. In some embodiments of any of the above aspects, the RNA is an inhibitory RNA directed to a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). In some embodiments of any of the above aspects, the nuclease is a nuclease (e.g., a TALEN, ZFN, or Cas, e.g., Cas9) directed to a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). 
     In some embodiments of any of the above aspects, the serotonin receptor small molecule inhibitor (e.g., antagonist) is a HTR1F antagonist listed in Table 2. 
     In some embodiments of any of the above aspects, the serotonin receptor small molecule inhibitor (e.g., antagonist) is a HTR2B antagonist listed in Table 2. 
     In some embodiments of any of the above aspects, the serotonin receptor small molecule inhibitor (e.g., antagonist) is a HTR2C antagonist listed in Table 2. 
     In some embodiments of any of the above aspects, the serotonin receptor small molecule inhibitor (e.g., antagonist) is a HTR3A antagonist listed in Table 2. 
     In some embodiments of any of the above aspects, the serotonin receptor small molecule inhibitor (e.g., antagonist) is a HTR6 antagonist listed in Table 2. 
     In some embodiments of any of the above aspects, the serotonin receptor small molecule inhibitor (e.g., antagonist) is a HTR7 antagonist listed in Table 2. 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor does not cross the blood brain barrier. In some embodiments, the serotonin receptor inhibitor or the serotonin receptor-specific inhibitor has been modified to prevent blood brain barrier crossing by conjugation to a targeting moiety, formulation in a particulate delivery system, addition of a molecular adduct, or through modulation of its size, polarity, flexibility, or lipophilicity. 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor does not have a direct effect on the central nervous system or gut. 
     In some embodiments of any of the above aspects, the serotonin receptor inhibitor or serotonin receptor-specific inhibitor decreases tumor volume, decreases tumor growth, decreases tumor innervation, decreases cancer cell proliferation, decreases cancer cell invasion, decreases cancer cell migration, decreases cancer cell metastasis, increases cancer cell death, increases cancer cell autophagy, increases time to recurrence, improves survival, increases the development of HEVs or TLOs, increases immune cell migration, increases immune cell proliferation, increases immune cell recruitment, increases immune cell tumor homing, decreases immune cell tumor egress, increases immune cell differentiation, increases immune cell activation, increases immune cell polarization, increases immune cell cytokine production, increases immune cell degranulation, increases immune cell maturation, increases immune cell ADCC, increases immune cell ADCP, increases immune cell antigen presentation, or decreases immune cell serotonin receptor expression (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HRT6, and/or HTR7). 
     In some embodiments of any of the above aspects, the immune cell is an effector T cell, a helper T cell (e.g., a CD4+ T cell), a cytotoxic T cell (e.g., a CD8+ T cell), aTh1 cell, a Th2 cell, a Th17 cell, a B cell, a natural killer (NK) cell, an innate lymphoid cell 1 (ILC1), an ILC2, an ILC3, a monocyte, a macrophage (e.g., an M1 or M2 macrophage), a dendritic cell, a neutrophil, a basophil, an eosinophil, an antigen presenting cell, or a myeloid derived suppressor cell. 
     In some embodiments of any of the above aspects, the immune cell is a macrophage (e.g., an M2 macrophage). In some embodiments of any of the above aspects, the method increases macrophage polarization (e.g., polarization to an M1 phenotype, e.g., polarization of an M2 macrophage toward an M1 phenotype). In some embodiments of any of the above aspects, the method increases macrophage ADCP. In some embodiments of any of the above aspects, the method increases one or more of macrophage migration, proliferation, recruitment, tumor homing, differentiation, activation, or antigen presentation. In some embodiments of any of the above aspects, the method decreases macrophage tumor egress and/or macrophage serotonin receptor expression (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HRT6, and/or HTR7). In some embodiments of any of the above aspects, the method increases macrophage production of pro-inflammatory cytokines. In some embodiments, the pro-inflammatory cytokine is IL-8. 
     In some embodiments of any of the above aspects, the immune cell is a monocyte. In some embodiments of any of the above aspects, the method increases monocyte activation. In some embodiments of any of the above aspects, the method increases one or more of monocyte migration, proliferation, recruitment, tumor homing, differentiation, polarization (e.g., polarization toward an inflammatory state), antigen presentation, or ADCP. In some embodiments of any of the above aspects, the method decreases monocyte tumor egress and/or monocyte serotonin receptor expression (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HRT6, and/or HTR7). In some embodiments of any of the above aspects, the method increases monocyte production of pro-inflammatory cytokines. In some embodiments, the pro-inflammatory cytokine is IL-8. 
     In some embodiments of any of the above aspects, the immune cell is an MDSC. In some embodiments of any of the above aspects, the method increases MDSC activation. In some embodiments of any of the above aspects, the method increases one or more of MDSC migration, proliferation, recruitment, tumor homing, differentiation, polarization (e.g., polarization toward an inflammatory state), antigen presentation, or ADCP. In some embodiments of any of the above aspects, the method decreases MDSC tumor egress and/or MDSC serotonin receptor expression (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HRT6, and/or HTR7). In some embodiments of any of the above aspects, the method increases MDSC production of pro-inflammatory cytokines. In some embodiments, the pro-inflammatory cytokine is IL-8. 
     In some embodiments of any of the above aspects, the immune cell is a dendritic cell. In some embodiments of any of the above aspects, the method increases dendritic cell activation. In some embodiments of any of the above aspects, the method increases one or more of dendritic cell migration, proliferation, recruitment, tumor homing, differentiation, polarization (e.g., polarization toward an inflammatory state), antigen presentation, or ADCP. In some embodiments of any of the above aspects, the method decreases dendritic cell tumor egress and/or dendritic cell serotonin receptor expression (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HRT6, and/or HTR7). In some embodiments of any of the above aspects, the method increases dendritic cell production of pro-inflammatory cytokines. In some embodiments, the pro-inflammatory cytokine is IL-8. 
     In some embodiments of any of the above aspects, the immune cell is a T cell (e.g., a CD4+ T cell or a CD8+ T cell). In some embodiments of any of the above aspects, the method increases T cell polarization (e.g., polarization toward an inflammatory phenotype). In some embodiments of any of the above aspects, the method increases T cell ADCP. In some embodiments of any of the above aspects, the method increases one or more of T cell migration, proliferation, recruitment, tumor homing, differentiation, activation, or antigen presentation. In some embodiments of any of the above aspects, the method decreases T cell tumor egress and/or T cell serotonin receptor expression (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HRT6, and/or HTR7). In some embodiments of any of the above aspects, the method increases T cell production of pro-inflammatory cytokines. In some embodiments, the pro-inflammatory cytokine is IL-8. 
     In some embodiments of any of the above aspects, the immune cell is a neutrophil. In some embodiments of any of the above aspects, the method increases neutrophil recruitment. In some embodiments of any of the above aspects, the method increases neutrophil tumor homing. In some embodiments of any of the above aspects, the method increases neutrophil activation. In some embodiments of any of the above aspects, the method increases neutrophil migration. In some embodiments, the method increases neutrophil recruitment, tumor homing, activation, and/or migration by increasing IL-8 production by T cells, dendritic cells, macrophages, monocytes, or MDSCs, increasing activation of T cells, dendritic cells, macrophages, monocytes, or MDSCs, or increasing polarization of T cells, dendritic cells, macrophages, monocytes, or MDSCs. 
     In some embodiments of any of the above aspects, the serotonin receptor is HTR1F, HTR2B, HTR2C, HTR3A, HRT6, or HTR7. 
     Definitions 
     As used herein, “administration” refers to providing or giving a subject a therapeutic agent (e.g., a serotonin receptor inhibitor), by any effective route. Exemplary routes of administration are described herein below. 
     As used herein, the term “agonist” refers to an agent (e.g., a small molecule or antibody) that increases receptor activity. An agonist may activate a receptor by directly binding to the receptor, by acting as a cofactor, by modulating receptor conformation (e.g., maintaining a receptor in an open or active state). An agonist may increase receptor activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. An agonist may induce maximal receptor activation or partial activation depending on the concentration of the agonist and its mechanism of action. 
     As used herein, the term “analog” refers to a protein of similar nucleotide or amino acid composition or sequence to any of the proteins or peptides of the invention, allowing for variations that do not have an adverse effect on the ability of the protein or peptide to carry out its normal function (e.g., bind to a receptor or promote synapse formation). Analogs may be the same length, shorter, or longer than their corresponding protein or polypeptide. Analogs may have about 60% (e.g., about 60%, about 62%, about 64%, about 66%, about 68%, about 70%, about 72%, about 74%, about 76%, about 78%, about 80%, about 82%, about 84%, about 86%, about 88%, about 90%, about 92%, about 94%, about 96%, about 98%, or about 99%) identity to the amino acid sequence of the naturally occurring protein or peptide. An analog can be a naturally occurring protein or polypeptide sequence that is modified by deletion, addition, mutation, or substitution of one or more amino acid residues. 
     As used herein, the term “antagonist” refers to an agent (e.g., a small molecule or antibody) that reduces or inhibits receptor activity. An antagonist may reduce receptor activity by directly binding to the receptor, by blocking the receptor binding site, by modulating receptor conformation (e.g., maintaining a receptor in a closed or inactive state). An antagonist may reduce receptor activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. An antagonist may also completely block or inhibit receptor activity. Antagonist activity may be concentration-dependent or -independent. 
     As used herein, the term “antibody” refers to a molecule that specifically binds to, or is immunologically reactive with, a particular antigen and includes at least the variable domain of a heavy chain, and normally includes at least the variable domains of a heavy chain and of a light chain of an immunoglobulin. Antibodies and antigen-binding fragments, variants, or derivatives thereof include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized, primatized, or chimeric antibodies, heteroconjugate antibodies (e.g., bi- tri- and quad-specific antibodies, diabodies, triabodies, and tetrabodies), single-domain antibodies (sdAb), epitope-binding fragments, e.g., Fab, Fab′ and F(ab′)2, Fd, Fvs, single-chain Fvs (scFv), rIgG, single-chain antibodies, disulfide-linked Fvs (sdFv), fragments including either a VL or VH domain, fragments produced by an Fab expression library, and anti-idiotypic (anti-Id) antibodies. Antibody molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule. Moreover, unless otherwise indicated, the term “monoclonal antibody” (mAb) is meant to include both intact molecules as well as antibody fragments (such as, for example, Fab and F(ab′)2 fragments) that are capable of specifically binding to a target protein. Fab and F(ab′)2 fragments lack the Fc fragment of an intact antibody. 
     The term “antigen-binding fragment,” as used herein, refers to one or more fragments of an immunoglobulin that retain the ability to specifically bind to a target antigen. The antigen-binding function of an immunoglobulin can be performed by fragments of a full-length antibody. The antibody fragments can be a Fab, F(ab′)2, scFv, SMIP, diabody, a triabody, an affibody, a nanobody, an aptamer, or a domain antibody. Examples of binding fragments encompassed by the term “antigen-binding fragment” of an antibody include, but are not limited to: (i) a Fab fragment, a monovalent fragment consisting of the V L , V H , C L , and C H 1 domains; (ii) a F(ab′) 2 fragment, a bivalent fragment including two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the V H  and C H 1 domains; (iv) a F V  fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb (Ward et al., Nature 341:544-546, 1989) including VH and VL domains; (vi) a dAb fragment that consists of a VH domain; (vii) a dAb that consists of a VH or a VL domain; (viii) an isolated complementarity determining region (CDR); and (ix) a combination of two or more isolated CDRs which may optionally be joined by a synthetic linker. Furthermore, although the two domains of the F V  fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain F V  (scFv)). These antibody fragments can be obtained using conventional techniques known to those of skill in the art, and the fragments can be screened for utility in the same manner as intact antibodies. Antigen-binding fragments can be produced by recombinant DNA techniques, enzymatic or chemical cleavage of intact immunoglobulins, or, in certain cases, by chemical peptide synthesis procedures known in the art. 
     As used herein, the term “cell type” refers to a group of cells sharing a phenotype that is statistically separable based on gene expression data. For instance, cells of a common cell type may share similar structural and/or functional characteristics, such as similar gene activation patterns and antigen presentation profiles. Cells of a common cell type may include those that are isolated from a common tissue (e.g., epithelial tissue, neural tissue, connective tissue, or muscle tissue) and/or those that are isolated from a common organ, tissue system, blood vessel, or other structure and/or region in an organism. 
     As used herein, a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In other embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally. 
     As used herein, the terms “effective amount,” “therapeutically effective amount,” and a “sufficient amount” of a composition, antibody, vector construct, viral vector, or cell described herein refer to a quantity sufficient to, when administered to a subject, including a mammal (e.g., a human), effect beneficial or desired results, including effects at the cellular level, tissue level, or clinical results, and, as such, an “effective amount” or synonym thereto depends upon the context in which it is being applied. For example, in the context of treating cancer it is an amount of the composition, antibody, vector construct, viral vector, or cell sufficient to achieve a treatment response as compared to the response obtained without administration of the composition, antibody, vector construct, viral vector, or cell. The amount of a given composition described herein that will correspond to such an amount will vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, weight) or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. Also, as used herein, a “therapeutically effective amount” of a composition, antibody, vector construct, viral vector, or cell of the present disclosure is an amount that results in a beneficial or desired result in a subject as compared to a control. As defined herein, a therapeutically effective amount of a composition, antibody, vector construct, viral vector, or cell of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response. 
     As used herein, the terms “increasing” and “decreasing” refer to modulating resulting in, respectively, greater or lesser amounts, of function, expression, or activity of a metric relative to a reference. For example, subsequent to administration of a serotonin receptor inhibitor in a method described herein, the amount of a marker of a metric (e.g., immune cell activation) as described herein may be increased in a subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 98% or more relative to the amount of the marker prior to administration. Generally, the metric is measured subsequent to administration at a time that the administration has had the recited effect, e.g., at least one week, one month, 3 months, or 6 months, after a treatment regimen has begun. 
     As used herein, the term “innervated” refers to a tissue (e.g., a tumor, lymph node, spleen, primary, secondary or tertiary lymphoid organ) that contains nerves. “Innervation” refers to the process of nerves entering a tissue. 
     As used herein, “locally” or “local administration” means administration at a particular site of the body intended for a local effect and not a systemic effect. Examples of local administration are epicutaneous, inhalational, intra-articular, intrathecal, intravaginal, intravitreal, intrauterine, intra-lesional administration, lymph node administration, intratumoral administration and administration to a mucous membrane of the subject, wherein the administration is intended to have a local and not a systemic effect. As used herein, the term “percent (%) sequence identity” refers to the percentage of amino acid (or nucleic acid) residues of a candidate sequence that are identical to the amino acid (or nucleic acid) residues of a reference sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity (e.g., gaps can be introduced in one or both of the candidate and reference sequences for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). Alignment for purposes of determining percent sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software, such as BLAST, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For example, a reference sequence aligned for comparison with a candidate sequence may show that the candidate sequence exhibits from 50% to 100% sequence identity across the full length of the candidate sequence or a selected portion of contiguous amino acid (or nucleic acid) residues of the candidate sequence. The length of the candidate sequence aligned for comparison purposes may be, for example, at least 30%, (e.g., 30%, 40, 50%, 60%, 70%, 80%, 90%, or 100%) of the length of the reference sequence. When a position in the candidate sequence is occupied by the same amino acid residue as the corresponding position in the reference sequence, then the molecules are identical at that position. 
     As used herein, a “pharmaceutical composition” or “pharmaceutical preparation” is a composition or preparation having pharmacological activity or other direct effect in the mitigation, treatment, or prevention of disease, and/or a finished dosage form or formulation thereof and which is indicated for human use. 
     As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms, which are suitable for contact with the tissues of a subject, such as a mammal (e.g., a human) without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio. 
     As used herein, the term “proliferation” refers to an increase in cell numbers through growth and division of cells. 
     As used herein, the term “reference” refers to a level, expression level, copy number, sample or standard that is used for comparison purposes. For example, a reference sample can be obtained from a healthy individual (e.g., an individual who does not have cancer). A reference level can be the level of expression of one or more reference samples. For example, an average expression (e.g., a mean expression or median expression) among a plurality of individuals (e.g., healthy individuals, or individuals who do not have cancer). In other instances, a reference level can be a predetermined threshold level, e.g., based on functional expression as otherwise determined, e.g., by empirical assays. 
     As used herein, the term “sample” refers to a specimen (e.g., blood, blood component (e.g., serum or plasma), urine, saliva, amniotic fluid, cerebrospinal fluid, tissue (e.g., placental or dermal), pancreatic fluid, chorionic villus sample, and cells) isolated from a subject. 
     As used herein, the terms “subject” and “patient” refer to an animal (e.g., a mammal, such as a human). A subject to be treated according to the methods described herein may be one who has been diagnosed with a particular condition, or one at risk of developing such conditions. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition. 
     “Treatment” and “treating,” as used herein, refer to the medical management of a subject with the intent to improve, ameliorate, stabilize (i.e., not worsen), prevent or cure a disease, pathological condition, or disorder. This term includes active treatment (treatment directed to improve the disease, pathological condition, or disorder), causal treatment (treatment directed to the cause of the associated disease, pathological condition, or disorder), palliative treatment (treatment designed for the relief of symptoms), preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder); and supportive treatment (treatment employed to supplement another therapy). Treatment also includes diminishment of the extent of the disease or condition; preventing spread of the disease or condition; delay or slowing the progress of the disease or condition; amelioration or palliation of the disease or condition; and remission (whether partial or total), whether detectable or undetectable. “Ameliorating” or “palliating” a disease or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented. 
     As used herein, the term “overexpressed” refers to a nucleic acid or polypeptide that is expressed or caused to be expressed or produced in a cell at a greater level than is normally expressed in the corresponding wild-type cell. For example, a serotonin receptor is “overexpressed” in an immune cell when the serotonin receptor is present at a higher level in the immune cell compared to the level in a healthy cell of the same tissue or cell type from the same species or individual. A serotonin receptor is overexpressed when serotonin receptor expression (e.g., expression of one or more serotonin receptors listed in Table 1) is increased by 1.1-fold or more (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0-fold or more) compared to a reference (e.g., a non-cancerous cell of the same type). 
     As used herein, the term “cancer” refers to a condition characterized by unregulated or abnormal cell growth. The terms “cancer cell,” “tumor cell,” and “tumor” refer to an abnormal cell, mass, or population of cells that result from excessive division that may be malignant or benign and all pre-cancerous and cancerous cells and tissues. 
     As used herein, the term “serotonin receptor-associated cancer” refers to a cancer that is associated with immune cells in which a serotonin receptor is expressed (e.g., immune cells that express one or more serotonin receptors (e.g., one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HRT6, and/or HTR7) or immune cells having increased expression of one or more serotonin receptors (e.g., one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HRT6, and/or HTR7)) compared to a reference (e.g., an immune cell from a subject that does not have cancer). The immune cells can be systemic immune cells or immune cells that have infiltrated the tumor (e.g., infiltrating T cells, monocytes, or M2 macrophages, tumor-resident macrophages, or myeloid derived suppressor cells). Serotonin receptor-associated cancers can be identified by assessing an immune cell or a biopsy of an immune-cell infiltrated tumor for immune cell serotonin receptor expression (e.g., gene or protein expression) and comparing it to serotonin receptor expression in a reference cell. 
     As used herein, the term “activation” refers to the response of an immune cell to a perceived insult. When immune cells become activated, they proliferate, secrete pro-inflammatory cytokines, differentiate, present antigens, become more polarized, and become more phagocytic and cytotoxic. Factors that stimulate immune cell activation include pro-inflammatory cytokines, pathogens, and non-self antigen presentation (e.g., antigens from pathogens presented by dendritic cells, macrophages, or B cells). 
     As used herein, the terms “antibody-dependent cell mediated cytotoxicity” and “antibody-dependent cellular toxicity” (ADCC) refer to the killing of an antibody-coated target cell by a cytotoxic effector cell through a non-phagocytic process, characterized by the release of the content of cytotoxic granules or by the expression of cell death-inducing molecules. ADCC is triggered through interaction of target-bound antibodies (belonging to IgG or IgA or IgE classes) with certain Fc receptors (FcRs), glycoproteins present on the effector cell surface that bind the Fc region of immunoglobulins (Ig). Effector cells that mediate ADCC include natural killer (NK) cells, innate lymphoid cells (ILCs) monocytes, macrophages, neutrophils, eosinophils and dendritic cells. 
     As used herein, the terms “antibody-dependent cell mediated phagocytosis” and “antibody-dependent cellular phagocytosis” (ADCP) refer to the phagocytosis (e.g., engulfment) of an antibody-coated target cell by immune cells (e.g., phagocytes). ADCP is triggered through interaction of target-bound antibodies (belonging to IgG or IgA or IgE classes) with certain Fc receptors (FcRs, e.g., FcγRIIa, FcγRIIIa, and FcγRI), glycoproteins present on the effector cell surface that bind the Fc region of immunoglobulins (Ig). Effector cells that mediate ADCP include monocytes, macrophages, neutrophils, and dendritic cells. 
     As used herein, the term “antigen presentation” refers to a process in which fragments of antigens are displayed on the cell surface of immune cells. Antigens are presented to T cells and B cells to stimulate an immune response. Antigen presenting cells include dendritic cells, B cells, and macrophages. Mast cells and neutrophils can also be induced to present antigens. 
     As used herein, the term “anti-inflammatory cytokine” refers to a cytokine produced or secreted by an immune cell that reduces inflammation. Immune cells that produce and secrete anti-inflammatory cytokines include T cells (e.g., Th cells) macrophages, B cells, and mast cells. Anti-inflammatory cytokines include IL4, IL-10, IL-11, IL-13, interferon alpha (IFNα) and transforming growth factor-beta (TGFβ). 
     As used herein, the term “chemokine” refers to a type of small cytokine that can induce directed chemotaxis in nearby cells. Classes of chemokines include CC chemokines, CXC chemokines, C chemokines, and CX3C chemokines. Chemokines can regulate immune cell migration and homing, including the migration and homing of monocytes, macrophages, T cells, mast cells, eosinophils, and neutrophils. Chemokines responsible for immune cell migration include CCL19, CCL21, CCL14, CCL20, CCL25, CCL27, CXCL12, CXCL13, CCR9, CCR10, and CXCR5. Chemokines that can direct the migration of inflammatory leukocytes to sites of inflammation or injury include CCL2, CCL3, CCL5, CXCL1, CXCL2, and CXCL8. 
     As used herein, the term “cytokine” refers to a small protein involved in cell signaling. Cytokines can be produced and secreted by immune cells, such as T cells, B cells, macrophages, and mast cells, and include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors. 
     As used herein, the term “cytokine production” refers to the expression, synthesis, and secretion (e.g., release) of cytokines by an immune cell. 
     As used herein, the term “cytotoxicity” refers to the ability of immune cells to kill other cells. Immune cells with cytotoxic functions release toxic proteins (e.g., perforin and granzymes) capable of killing nearby cells. Natural killer cells, ILCs, and cytotoxic T cells (e.g., CD8+ T cells) are the primary cytotoxic effector cells of the immune system, although dendritic cells, neutrophils, eosinophils, mast cells, basophils, macrophages, and monocytes have been shown to have cytotoxic activity. 
     As used herein, the term “differentiation” refers to the developmental process of lineage commitment. A “lineage” refers to a pathway of cellular development, in which precursor or “progenitor” cells undergo progressive physiological changes to become a specified cell type having a characteristic function (e.g., nerve cell, immune cell, or endothelial cell). Differentiation occurs in stages, whereby cells gradually become more specified until they reach full maturity, which is also referred to as “terminal differentiation.” A “terminally differentiated cell” is a cell that has committed to a specific lineage, and has reached the end stage of differentiation (i.e., a cell that has fully matured). By “committed” or “differentiated” is meant a cell that expresses one or more markers or other characteristic of a cell of a particular lineage. 
     As used herein, the term “degranulation” refers to a cellular process in which molecules, including antimicrobial and cytotoxic molecules, are released from intracellular secretory vesicles called granules. Degranulation is part of the immune response to pathogens and invading microorganisms by immune cells such as granulocytes (e.g., neutrophils, basophils, and eosinophils), mast cells, and lymphocytes (e.g., natural killer cells, ILCs, and cytotoxic T cells). The molecules released during degranulation vary by cell type and can include molecules designed to kill the invading pathogens and microorganisms or to promote an immune response, such as inflammation. 
     As used herein, the term “immune dysregulation” refers to a condition in which the immune system is disrupted or responding to an insult. Immune dysregulation includes aberrant activation (e.g., autoimmune disease), activation in response to an injury or disease (e.g., disease-associated inflammation), and activation in response to a pathogen or infection (e.g., parasitic infection). Immune dysregulation also includes under-activation of the immune system (e.g., failure to mount an immune response to cancer cells or immunosuppression). Immune dysregulation can be treated using the methods and compositions described herein to direct immune cells to carry out beneficial functions and reduce harmful activities (e.g., promoting activation and cytotoxicity in subjects with cancer and reducing activation and pro-inflammatory cytokine secretion in subjects with autoimmune disease). 
     As used herein, the term “modulating an immune response” refers to any alteration in a cell of the immune system or any alteration in the activity of a cell involved in the immune response. Such regulation or modulation includes an increase or decrease in the number of various cell types, an increase or decrease in the activity of these cells, or any other changes that can occur within the immune system. Cells involved in the immune response include, but are not limited to, T lymphocytes (T cells), B lymphocytes (B cells), natural killer (NK) cells, innate lymphoid cells (ILCs), macrophages, eosinophils, mast cells, dendritic cells and neutrophils. In some cases, “modulating” the immune response means the immune response is stimulated or enhanced, and in other cases “modulating” the immune response means suppression of the immune system. 
     As used herein, the term “lymph node egress” refers to immune cell exit from the lymph nodes, which occurs during immune cell recirculation. Immune cells that undergo recirculation include lymphocytes (e.g., T cells, B cells, and natural killer cells), which enter the lymph node from blood to survey for antigen and then exit into lymph and return to the blood stream to perform antigen surveillance. 
     As used herein, the term “lymph node homing” refers to directed migration of immune cells to a lymph node. Immune cells that return to lymph nodes include T cells, B cells, macrophages, and dendritic cells. 
     As used herein, the term “migration” refers to the movement of immune cells throughout the body. Immune cells can migrate in response to external chemical and mechanical signals. Many immune cells circulate in blood including peripheral blood mononuclear cells (e.g., lymphocytes such as T cells, B cells, and natural killer cells), monocytes, macrophages, dendritic cells, and polymorphonuclear cells (e.g., neutrophils and eosinophils). Immune cells can migrate to sites of infection, injury, or inflammation, back to the lymph nodes, or to tumors or cancer cells. 
     As used herein, the term “phagocytosis” refers to the process in which a cell engulfs or ingests material, such as other cells or parts of cells (e.g., bacteria), particles, or dead or dying cells. A cell that capable of performing this function is called a phagocyte. Immune phagocytes include neutrophils, monocytes, macrophages, mast cells, B cells, eosinophils, and dendritic cells. 
     As used herein, the term “polarization” refers to the ability of an immune cell to shift between different functional states. A cell that is moving toward one of two functional extremes is said to be in the process of becoming more polarized. The term polarization is often used to refer to macrophages, which can shift between states known as M1 and M2. M1, or classically activated, macrophages secrete pro-inflammatory cytokines (e.g., IL-12, TNF, IL-6, IL-8, IL-1B, MCP-1, and CCL2), are highly phagocytic, and respond to pathogens and other environmental insults. M1 macrophages can also be detected by expression of Nos2. M2, or alternatively activated, macrophages secrete a different set of cytokines (e.g., IL-10) and are less phagocytic. M2 macrophages can detected by expression of Arg1, IDO, PF4, CCL24, IL10, and IL4Rα. Cells become polarized in response to external cues such as cytokines, pathogens, injury, and other signals in the tissue microenvironment. 
     As used herein, the term “pro-inflammatory cytokine” refers to a cytokine secreted from immune cells that promotes inflammation. Immune cells that produce and secrete pro-inflammatory cytokines include T cells (e.g., Th cells) macrophages, B cells, and mast cells. Pro-inflammatory cytokines include interleukin-1 (IL-1, e.g., IL-1β), IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-18, tumor necrosis factor (TNF, e.g., TNFα), interferon gamma (IFNγ), and granulocyte macrophage colony stimulating factor (GMCSF). 
     As used herein, the term “pro-survival cytokine” refers to a cytokine that promotes the survival of immune cells (e.g., T cells). Pro-survival cytokines include IL-2, IL-4, IL-6, IL-7, and IL-15. 
     As used herein, the term “recruitment” refers to the re-distribution of immune cells to a particular location (e.g., the site of injury, disease, or inflammation). Immune cells that can undergo this re-distributed and be recruited to sites of injury or disease include monocytes, macrophages, T cells, B cells, dendritic cells, and natural killer cells. 
     The term “serotonin receptor inhibitory antibody” refers to antibodies that are capable of binding to a serotonin receptor and inhibiting or reducing serotonin receptor function and/or attenuating one or more signal transduction pathways mediated by a serotonin receptor. For example, serotonin receptor inhibitory antibodies may disrupt serotonin receptor activation or block or reduce the dimerization of a serotonin receptor. The term “serotonin receptor-specific inhibitory antibody” refers to antibodies that bind specifically to a single serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HRT6, or HTR7) and inhibit or reduce serotonin receptor function and/or attenuate one or more signal transduction pathways mediated by a serotonin receptor. Serotonin receptor inhibitory antibodies and serotonin receptor-specific inhibitory antibodies inhibit or reduce serotonin receptor function and/or attenuate one or more serotonin receptor-mediated signal transduction pathways by at least 10% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more). 
     As used herein, the term “serotonin receptor inhibitor” refers to an agent that inhibits or reduces serotonin receptor function or signaling. Serotonin receptor inhibitors include serotonin receptor inhibitory antibodies, serotonin receptor small molecule inhibitors, serotonin receptor signaling inhibitors, and inhibitory RNAs and nucleases directed to a serotonin receptor that reduce or inhibit serotonin receptor expression, serotonin receptor function, or signal transduction downstream of a serotonin receptor. Serotonin receptor inhibitors reduce serotonin receptor function or signaling by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more). 
     As used herein, the term “serotonin receptor-specific inhibitor” refers to a serotonin receptor inhibitor that selectively inhibits or reduces the function or signaling of a single type of serotonin receptor without directly reducing or inhibiting the function of other serotonin receptors. Serotonin receptor-specific inhibitors include serotonin receptor-specific inhibitory antibodies, inhibitory RNAs and nucleases directed to a serotonin receptor, and serotonin receptor-selective small molecule inhibitors. Serotonin receptor-specific inhibitors reduce serotonin receptor function or signaling by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more). 
     As used herein, the term “serotonin receptor function blocker” refers to a type of serotonin receptor inhibitor that reduces or inhibits serotonin receptor function by reducing the expression of a serotonin receptor, reducing serotonin receptor activation, or reducing serotonin receptor function. Exemplary serotonin receptor function blockers include serotonin receptor inhibitory antibodies and small molecule serotonin receptor inhibitors. Serotonin receptor function blockers reduce serotonin receptor function by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more). 
     As used herein, the term “serotonin receptor signaling inhibitor” refers to a type of serotonin receptor inhibitor that reduces or inhibits the intracellular signaling that is downstream of serotonin receptor activation or interaction with a binding partner. Exemplary serotonin receptor signaling inhibitors include small molecules and inhibitory RNAs directed to molecules in downstream signaling cascades (e.g., ERK1, ERK2, or MAPK). Serotonin receptor signaling inhibitors reduce downstream signaling by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more). 
     As used herein, the terms “serotonin receptor small molecule inhibitor” and “serotonin receptor small molecule antagonist” refer to a small molecule that reduces or inhibits function, activation, or signaling of a serotonin receptor (e.g., one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HRT6, and/or HTR7) and has an IC50 of 10 μM or lower. The serotonin receptor antagonist may be selective for a single serotonin receptor (e.g., primarily binds to and inhibits or reduces the function or activation of a single serotonin receptor compared to other serotonin receptors), or the serotonin receptor antagonist may exhibit similar inhibitory effects on multiple serotonin receptors (e.g., may bind to and reduce the function or activation of more than one serotonin receptor listed in Table 1). Serotonin receptor antagonists for use in the methods and compositions described herein are provided in Table 2. 
     As used herein, an agent that “does not cross the blood brain barrier” is an agent that does not significantly cross the barrier between the peripheral circulation and the brain and spinal cord. This can also be referred to as a “blood brain barrier impermeable” agent. Agents will have a limited ability to cross the blood brain barrier if they are not lipid soluble or have a molecular weight of over 600 Daltons. Agents that typically cross the blood brain barrier can be modified to become blood brain barrier impermeable based on chemical modifications that increase the size or alter the hydrophobicity of the agent, packaging modifications that reduce diffusion (e.g., packaging an agent within a microparticle or nanoparticle), and conjugation to biologics that direct the agent away from the blood brain barrier (e.g., conjugation to a pancreas-specific antibody). An agent that does not cross the blood brain barrier is an agent for which 30% or less (e.g., 30%, 25%, 20%, 15%, 10%, 5%, 2% or less) of the administered agent crosses the blood brain barrier. 
     As used herein, an agent that “does not have a direct effect on the central nervous system (CNS) or gut” is an agent that does not directly alter neurotransmission, neuronal numbers, or neuronal morphology in the CNS or gut when administered according to the methods described herein. This may be assessed by administering the agents to animal models and performing electrophysiological recordings or immunohistochemical analysis. An agent will be considered not to have a direct effect on the CNS or gut if administration according to the methods described herein has an effect on neurotransmission, neuronal numbers, or neuronal morphology in the CNS or gut that is 50% or less (e.g., 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or less) of the effect observed if the same agent is administered directly to the CNS or gut. 
     As used herein, the term “migraine” refers to a neurological disorder characterized by moderate to severe headaches often accompanied by nausea, vomiting, or sensitivity to light. 
     As used herein, the term “neuropsychiatric disorder” refers to a psychiatric or mental disorder that may cause suffering or an impaired ability to function. A neuropsychiatric disorder is a syndrome characterized by clinically significant disturbance in an individual&#39;s cognition, emotion regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental functioning. Neuropsychiatric disorders may be diagnosed by psychiatrists, psychologists, neurologists, or physicians. Neuropsychiatric disorders include mood disorders (e.g., depression, bipolar depression, major depressive disorder), psychotic disorders (e.g., schizophrenia, schizoaffective disorder), personality disorders (e.g., borderline personality disorder, obsessive compulsive personality disorder, narcissistic personality disorder), eating disorders, sleep disorders, sexual disorders, anxiety disorders (e.g., generalized anxiety disorder, social anxiety disorder, post-traumatic stress disorder), developmental disorders (e.g., autism, attention deficit disorder, attention deficit hyperactivity disorder), benign forgetfulness, childhood learning disorders, Alzheimer&#39;s disease, addiction, and others listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM). 
     As used herein, the term “neuronal growth factor modulator” refers to an agent that regulates neuronal growth, development, or survival. Neuronal growth factors include proteins that promote neurogenesis, neuronal growth, and neuronal differentiation (e.g., neurotrophic factors NGF, NT3, BDNF, CNTF, and GDNF), proteins that promote neurite outgrowth (e.g., axon or dendrite outgrowth or stabilization), or proteins that promote synapse formation (e.g., synaptogenesis, synapse assembly, synaptic adhesion, synaptic maturation, synaptic refinement, or synaptic stabilization). These processes lead to innervation of tissue, including neural tissue, muscle, lymph nodes and tumors, and the formation of synaptic connections between two or more neurons and between neurons and non-neural cells (e.g., tumor cells). A neuronal growth factor modulator may block one or more of these processes (e.g., through the use of antibodies that block neuronal growth factors or their receptors) or promote one or more of these processes (e.g., through the use of these proteins or analogs or peptide fragments thereof). Exemplary neuronal growth factors are listed in Table 14. Neuronal growth factor modulators decrease or increase neurite outgrowth, innervation, synapse formation, or any of the aforementioned processes by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more). 
     As used herein, the term “neurotransmission modulator” refers to an agent that either induces or increases neurotransmission or decreases or blocks neurotransmission. Neurotransmission modulators can increase or decrease neurotransmission by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. Exemplary neurotransmitters and neurotransmitter receptors are listed in Tables 9 and 10. Neurotransmission modulators may increase neurotransmission by increasing neurotransmitter synthesis or release, preventing neurotransmitter reuptake or degradation, increasing neurotransmitter receptor activity, increasing neurotransmitter receptor synthesis or membrane insertion, decreasing neurotransmitter degradation, and regulating neurotransmitter receptor conformation. Neurotransmission modulators that increase neurotransmission include neurotransmitters and analogs thereof and neurotransmitter receptor agonists. Neurotransmission modulators may decrease neurotransmission by decreasing neurotransmitter synthesis or release, increasing neurotransmitter reuptake or degradation, decreasing neurotransmitter receptor activity, decreasing neurotransmitter receptor synthesis or membrane insertion, increasing neurotransmitter degradation, regulating neurotransmitter receptor conformation, and disrupting the pre- or postsynaptic machinery. Neurotransmission modulators that decrease or block neurotransmission include antibodies that bind to or block the function of neurotransmitters, neurotransmitter receptor antagonists, and toxins that disrupt synaptic release. As used herein, “neurotransmission blocker” refers to a neurotransmission modulator that reduces or blocks neurotransmission. 
    
    
     DETAILED DESCRIPTION 
     Described herein are compositions and methods for the treatment of cancer in a subject (e.g., a mammalian subject, such as a human) by administering serotonin receptor inhibitors. serotonin receptor inhibitors include inhibitors specific to serotonin receptor (e.g., HTR1F, HTR2B, HTR2C, HTR3A, HRT6, or HTR7-specific inhibitory antibodies) and non-specific inhibitors that could potentially affect other proteins due to their having shared binding partners or signaling pathways with serotonin receptors. These methods and compositions provide new mechanistic approaches for treating cancer. 
     Serotonin Receptors 
     Serotonin receptors are a family of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. The serotonin receptors may be activated by the neurotransmitter serotonin, which acts as their natural ligand. Serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine/norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P, among others. They also influence various biological and neurological processes such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation 
     The present invention relates to the surprising discovery that serotonin receptors (especially HTR1F, HTR2B, HTR2C, HRT3A, HTR6, and HTR7) are highly expressed on macrophages, dendritic cells, and T cells. The addition of serotonin receptor agonists to cultured M2 macrophages reduced macrophage production of the pro-inflammatory cytokine IL-8. Therefore, the use of serotonin receptor antagonists may increase immune cell production of IL-8, which is the primary cytokine involved in driving neutrophil recruitment and activation. These findings indicate that inhibition of serotonin receptors can be used as a therapeutic strategy for treating cancer by engaging the immune system. 
     Serotonin Receptor Inhibitors 
     Serotonin receptor inhibitors described herein can reduce or inhibit serotonin receptor function or signaling in order to treat cancer. Serotonin receptor inhibitors can be grouped into categories based on their mechanism of action and their effect on serotonin receptors: 1) serotonin receptor-specific inhibitors (e.g., inhibitors that only disrupt the function or signaling of a single type of serotonin receptor, such as HTR1F, HTR2B, HTR2C, HRT3A, HTR6, and HTR7-specific inhibitory antibodies or serotonin receptor-selective small molecule inhibitors (e.g., antagonists)), 2) serotonin receptor function blockers (e.g., inhibitors that prevent serotonin receptor dimerization or activation, e.g., serotonin receptor inhibitory antibodies and serotonin receptor small molecule inhibitors (e.g., antagonists) that inhibit more than one serotonin receptor), 3) serotonin receptor signaling inhibitors (e.g., inhibitors that disrupt downstream signaling pathways or intracellular or extracellular events that occur after activation of serotonin receptors), and 4) neurotransmission blockers (e.g., neurotoxins that reduce nerve activity or neurotransmitter release). 
     Serotonin Receptor-Specific Inhibitors 
     In some embodiments, the serotonin receptor inhibitor is a serotonin receptor-specific inhibitor. Serotonin receptor-specific inhibitors selectively reduce or inhibit the function, expression, or signaling of a single serotonin receptor (e.g., a serotonin receptor in Table 1, e.g., HTR1F, HTR2B, HTR2C, HRT3A, HTR6, or HTR7) without directly affecting other serotonin receptors. Serotonin receptor-specific inhibitors include serotonin-specific inhibitory antibodies or antigen binding fragments thereof, inhibitory RNAs directed to a serotonin receptor, nucleases directed to a serotonin receptor, or serotonin receptor-selective small molecule inhibitors (e.g., antagonists). Serotonin receptor-specific inhibitors can reduce serotonin receptor function, expression, or signaling by 5% or more (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more). 
     In some embodiments, the serotonin receptor inhibitory antibody is a serotonin receptor-specific inhibitory antibody or an antigen binding fragment thereof that binds to a serotonin receptor and reduces or inhibits serotonin receptor function. Serotonin receptor-specific inhibitory antibodies include antibodies having one or more of the following functional properties: do not have agonistic activity (e.g., do not activate the serotonin receptor); induce antibody-dependent cell killing of the cell expressing the serotonin receptor (e.g., antibody-dependent cell killing by Natural Killer (NK) cells, monocytes, macrophages, neutrophils, dendritic cells, or eosinophils); induce phagocytosis of the cell expressing the serotonin receptor (e.g., macrophage phagocytosis of the immune cell); induce opsonization of the cell expressing the serotonin receptor; prevent dimerization of the serotonin receptor (e.g., the antibody is a monovalent antibody or an antibody with a single heavy chain); induce downregulation of serotonin receptor on the cell surface (e.g., hyper-crosslink or cluster the receptor to induce internalization and degradation, e.g., the antibody is a polyvalent antibody); or bind to an extracellular region of the multi-pass transmembrane portion of the serotonin receptor. In some embodiments, the serotonin receptor-specific inhibitory antibody is a HTR1F-specific inhibitory antibody and binds to or blocks an extracellular domain of HTR1F (amino acids 1-29, 84-97, 162-178, and/or 312-329) or amino acids 99-108 and/or 306-310 of HTR1F. In some embodiments, the serotonin receptor-specific inhibitory antibody is a HTR2B-specific inhibitory antibody and binds to or blocks one or more of residues D135, V136, S139, T140, K211, F217, W337, F340, N344, or Y370 of HTR2B. In some embodiments, the serotonin receptor-specific inhibitory antibody is a HTR2C-specific inhibitory antibody and binds to or blocks one or more of residues P159, S456, or V458 of HTR2C. In some embodiments, the serotonin receptor-specific inhibitory antibody is a HTR3A-specific inhibitory antibody and binds to or blocks an extracellular domain of HTR3A (amino acids 24-241, 293-302, and/or 476-478), amino acids 178, 432, 436, and/or 440 of HTR3A, or the expansion of amino acid 306(G) in the 5HTR3A-AL isoform. In some embodiments, the serotonin receptor-specific inhibitory antibody is a HTR6-specific inhibitory antibody and binds to or blocks an extracellular domain of HTR6 (amino acids 1-34, 86-100, 168-184, and/or 291-295). In some embodiments, the serotonin receptor-specific inhibitory antibody is a HTR7-specific inhibitory antibody and binds to or blocks one or more glycosylation sites (e.g., glycosylation sites 5 or 66) or a lipidation site (e.g., lipidation site 401) of HTR7. Antibodies having one or more of these functional properties are routinely screened and selected once the desired functional property is identified herein (e.g., by screening of phage display or other antibody libraries). 
     In some embodiments, the serotonin receptor-specific inhibitor is a small molecule inhibitor (e.g., antagonist) that is selective for a specific serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., an HTR1F-selective inhibitor, an HTR2B-selective inhibitor, an HTR2C-selective inhibitor, an HTR3A-selective inhibitor, an HTR6-selective inhibitor, or an HTR7-selective inhibitor). Serotonin receptor-selective small molecule inhibitors for use in the methods and compositions described herein are included in Table 2. 
     In some embodiments, the serotonin receptor-specific inhibitor is an inhibitory RNA (e.g., small interfering RNA (siRNA), short hairpin RNA (shRNA), or microRNA (miRNA)) directed to a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HRT3A, HTR6, or HTR7). 
     In some embodiments, the serotonin receptor-specific inhibitor is a nuclease (e.g., a transcription activator-like effector nuclease (TALEN), zinc finger nuclease (ZFN), or CRISPR associated protein (Cas), e.g., Cas9) directed to a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HRT3A, HTR6, or HTR7). 
     Serotonin Receptor Function Blockers 
     In some embodiments, the serotonin receptor inhibitor is a serotonin receptor function blocker. Serotonin receptor function blockers reduce or inhibit serotonin receptor function by reducing serotonin receptor expression or preventing or reducing serotonin receptor activation. Serotonin receptor function blockers include serotonin receptor-specific inhibitors that reduce or inhibit serotonin receptor function or expression (e.g., serotonin receptor-specific inhibitory antibodies or antigen binding fragments thereof, inhibitory RNA or nucleases directed to a serotonin receptor, or serotonin receptor-selective small molecule inhibitors (e.g., antagonists)), or serotonin receptor inhibitory antibodies or antigen binding fragments thereof or small molecules that bind to or inhibit more than one serotonin receptor. 
     In some embodiments, the serotonin receptor inhibitory antibodies bind to or antagonize more than one serotonin receptor (e.g., at least two or more serotonin receptors listed in Table 1) and have one or more of the following functional properties: do not have agonistic activity (e.g., do not activate the serotonin receptors); induce antibody-dependent cell killing of the cells expressing the serotonin receptors (e.g., antibody-dependent cell killing by NK cells, monocytes, macrophages, neutrophils, dendritic cells, or eosinophils); induce phagocytosis of the cells expressing the serotonin receptors (e.g., macrophage phagocytosis of the immune cell); induce opsonization of the cells expressing the serotonin receptors; prevent dimerization of the serotonin receptors (e.g., the antibody is a monovalent antibody or an antibody with a single heavy chain); induce downregulation of serotonin receptors on the cell surface (e.g., hyper-crosslink or cluster the ligand to induce internalization and degradation, e.g., the antibody is a polyvalent antibody); or bind to an extracellular region of the multi-pass transmembrane portion of the serotonin receptors. Antibodies or antibody-like molecules having one or more of these functional properties are routinely screened and selected once the desired functional property is identified herein (e.g., by screening of phage display or other antibody libraries). 
     In some embodiments, the serotonin receptor function blocker is a non-selective serotonin receptor inhibitor (e.g., an antagonist that inhibits two or more serotonin receptors listed in Table 1). Non-selective serotonin receptor inhibitors for use in the methods and compositions described herein are included in Table 2. 
     Serotonin Receptor Signaling Inhibitors 
     In some embodiments, the serotonin receptor inhibitor is a serotonin receptor signaling inhibitor. Serotonin receptor signaling inhibitors include agents that reduce or inhibit signaling that occurs downstream of serotonin receptor activation, such as small molecule inhibitors of intracellular signaling cascades (e.g., inhibitors of G protein signaling, beta arrestin signaling, the phosphatidylinositol-calcium second messenger system, ERK1, ERK2, or MAP kinase) and inhibitory RNAs directed to components of such downstream signaling cascades (e.g., inhibitory RNAs directed to one or more components of G protein signaling, beta arrestin signaling, the phosphatidylinositol-calcium second messenger system, ERK1, ERK2, or MAP kinase). Exemplary small molecule serotonin receptor signaling inhibitors for use in the methods and compositions described herein are provided in Table 3. 
     Neurotransmission Blockers 
     In some embodiments, the serotonin receptor inhibitor is a neurotransmission blocker. Neurotransmission blockers decrease or block neurotransmission by decreasing neurotransmitter synthesis or release, increasing neurotransmitter reuptake or degradation, decreasing neurotransmitter receptor activity and/or disrupting the pre or postsynaptic machinery. In some embodiments, the neurotransmission blocker is a neurotoxin that inhibits or reduces neuronal activity or neurotransmitter release. In some embodiments, the neurotoxin is a neurotoxin listed in Table 13. In some embodiments, the neurotoxin is trichothecene mycotoxin deoxynivalenol (DON) or pertussis toxin. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 SEROTONIN RECEPTORS 
               
            
           
           
               
               
               
            
               
                   
                   
                 Accession Number 
               
               
                   
                 Receptor 
                 (Entrez Gene ID) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 HTR1A 
                 3350 
               
               
                   
                 HTR1B 
                 3351 
               
               
                   
                 HTR1D 
                 3352 
               
               
                   
                 HTR1E 
                 3354 
               
               
                   
                 HTR1F 
                 3355 
               
               
                   
                 HTR2A 
                 3356 
               
               
                   
                 HTR2B 
                 3357 
               
               
                   
                 HTR2C 
                 3358 
               
               
                   
                 HTR3A 
                 3359 
               
               
                   
                 HTR3B 
                 9177 
               
               
                   
                 HTR3C 
                 170572 
               
               
                   
                 HTR3D 
                 200909 
               
               
                   
                 HTR3E 
                 285242 
               
               
                   
                 HTR4 
                 3360 
               
               
                   
                 HTR5A 
                 3361 
               
               
                   
                 HRT5BP 
                 645694 
               
               
                   
                 HTR6 
                 3362 
               
               
                   
                 HTR7 
                 3365 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 SMALL MOLECULE SEROTONIN RECEPTOR INHIBITORS 
               
            
           
           
               
               
            
               
                 Receptor 
                 Inhibitors 
               
               
                   
               
               
                 HTR1A 
                 pindolol, tertatolol, alprenolol, AV-965, BMY-7,378, cyanopindolol,  
               
               
                 antagonists 
                 dotarizine, flopropione, GR-46,611, iodocyanopindolol, isamoltane, lecozotan,  
               
               
                   
                 mefway, methiothepin, methysergide, MPPF, NAN-190, oxprenolol, pindobind, 
               
               
                   
                 propanolol, risperidone, robalzotan, SB-649,915,  
               
               
                   
                 SDZ-216,525, spiperone, spiramide, spiroxatrine, UH-301,  
               
               
                   
                 WAY-100,135, WAY-100,635, and xylamidine 
               
               
                 HTR1B  
                 methiothepin, yohimbine, metergoline, aripiprazole, isamoltane, AR-A000002, 
               
               
                 antagonists 
                 SB-216,641, SB-224,289, GR-127,935, SB-236,057 
               
               
                 HTR1D  
                 ziprasidone, methiothepin, yohimbine, metergoline, ergotamine, BRL-15572, 
               
               
                 antagonists 
                 vortioxetine, GR-127,935, LY-310,762, LY-367,642, LY-456,219, and LY- 
               
               
                   
                 456,220 
               
               
                 HTR1F  
                 CHEMBL3633184, CHEMBL584046, CHEMBL576315, CHEMBL565552, 
               
               
                 antagonists 
                 CHEMBL571858, CHEMBL46187, CHEMBL178870, CHEMBL180606 
               
               
                 HTR2A  
                 cyproheptadine, methysergide, quetiapine, nefazodone, olanzapine, 
               
               
                 antagonists 
                 asenapine, pizotifen, LY-367,265, AMDA, hydroxyzine, 5-MeO-NBpBrT, and 
               
               
                   
                 niaprazine 
               
               
                 HTR2B  
                 Methysergide Maleate, Vabicaserin hydrochloride, CHEMBL2392349, 
               
               
                 antagonists 
                 CHEMBL3310123, CHEMBL21343, CHEMBL2392351, CHEMBL365882, 
               
               
                   
                 CHEMBL3601563, CHEMBL184717, CHEMBL185376, CHEMBL270177, 
               
               
                   
                 CHEMBL364863, CHEMBL198949, CHEMBL422931, CHEMBL2322611, 
               
               
                   
                 CHEMBL3099899, CHEMBL276393, CHEMBL2022867, CHEMBL216228, 
               
               
                   
                 CHEMBL584554, CHEMBL1368005, CHEMBL3287218, CHEMBL2426677, 
               
               
                   
                 CHEMBL3264204, CHEMBL3394201, CHEMBL595449, CHEMBL1922539, 
               
               
                   
                 CHEMBL1922538, CHEMBL469668, CHEMBL1922537, agomelatine, 
               
               
                   
                 aripiprazole, sarpogrelate, lisuride, tegaserod, metadoxine, RS-127,445, SDZ 
               
               
                   
                 SER-082, EGIS-7625, PRX-08066, SB-200,646, SB-204,741, SB-206,553, 
               
               
                   
                 SB-215,505, SB-228,357, LY-266,097, and LY-272,015 
               
               
                 HTR2C  
                 CHEMBL14255, CHEMBL2169982, CHEMBL14276, CHEMBL14368, 
               
               
                 antagonists 
                 CHEMBL586213, CHEMBL2169978, CHEMBL2169979, CHEMBL325674, 
               
               
                   
                 CHEMBL2169985, CHEMBL364005, CHEMBL2169991, CHEMBL187756, 
               
               
                   
                 CHEMBL326538, CHEMBL373084, CHEMBL189118, CHEMBL184717, 
               
               
                   
                 CHEMBL194305, CHEMBL575270, CHEMBL198949, CHEMBL515307, 
               
               
                   
                 CHEMBL573521, CHEMBL595301, CHEMBL195351, CHEMBL476006, 
               
               
                   
                 CHEMBL2169990, CHEMBL605938, CHEMBL113956, CHEMBL193473, 
               
               
                   
                 CHEMBL115076, CHEMBL196667, CHEMBL194837, CHEMBL116463, 
               
               
                   
                 CHEMBL325516, CHEMBL196581, CHEMBL117537, CHEMBL194691, 
               
               
                   
                 CHEMBL267615, CHEMBL196196, CHEMBL197245, CHEMBL217820, 
               
               
                   
                 CHEMBL198361, CHEMBL197050, CHEMBL2169981, CHEMBL605292, 
               
               
                   
                 CHEMBL574403, CHEMBL577570, CHEMBL216314, CHEMBL215660, 
               
               
                   
                 CHEMBL194046, CHEMBL654, CHEMBL1712, CHEMBL1200492, 
               
               
                   
                 CHEMBL479, CHEMBL85, CHEMBL715, CHEMBL831, CHEMBL1710, 
               
               
                   
                 CHEMBL1200426, CHEMBL908, agomelatine, CPC, eltoprazine, 
               
               
                   
                 etoperidone, fluoxetine, FR-260,010, LU AA24530, methysergide, 
               
               
                   
                 nefazodone, norfluoxetine, 0-desmethyltramadol, RS-102,221, SB-200,646, 
               
               
                   
                 SB-221,284, SB-242,084, SDZ SER-082, tramadol, and trazodone 
               
               
                 HTR3A  
                 Ondansetron, palonosetron hydrochloride, alosetron hydrochloride, 
               
               
                 antagonists 
                 metoclopramide hydrochloride, granisetron hydrochloride, vortioxetine 
               
               
                   
                 hydrobromide, dolasetron mesylate, ondansetron hydrochloride, 
               
               
                   
                 CHEMBL3262129, CHEMBL2204360, CHEMBL3262135, CHEMBL3262143, 
               
               
                   
                 CHEMBL519240, CHEMBL509540, CHEMBL2448556, CHEMBL2426097, 
               
               
                   
                 CHEMBL3262125, CHEMBL2426072, CHEMBL3262144, CHEMBL2418364, 
               
               
                   
                 CHEMBL1277561, CHEMBL2179529, CHEMBL3262171, CHEMBL2205362, 
               
               
                   
                 CHEMBL3823832, CHEMBL479683, CHEMBL1939782, CHEMBL2151572, 
               
               
                   
                 CHEMBL470432, CHEMBL6437, CHEMBL93240, CHEMBL2087445, 
               
               
                   
                 CHEMBL2087440, CHEMBL2087453, CHEMBL2087443, CHEMBL2087442, 
               
               
                   
                 CHEMBL2087441, CHEMBL2086583, CHEMBL2087454, CHEMBL2087448, 
               
               
                   
                 CHEMBL2086584, CHEMBL2087458, CHEMBL2087456, CHEMBL2087444, 
               
               
                   
                 CHEMBL2087450, CHEMBL2087452, CHEMBL2086585, CHEMBL2087446, 
               
               
                   
                 CHEMBL2086404, CHEMBL2087438, CHEMBL2087437, CHEMBL2086582, 
               
               
                   
                 CHEMBL2087457, CHEMBL2087447, CHEMBL2087451, CHEMBL2087439, 
               
               
                   
                 CHEMBL2087459, CHEMBL2087449, dolasetron, granisetron, ondansetron, 
               
               
                   
                 palonosetron, tropisetron, alosetron, cilanosetron, mirtazapine, AS-8112, 
               
               
                   
                 bantopride, metroclopramide, renzapride, zacopride, mianserin, vortioxetine, 
               
               
                   
                 clozapine, olanzapine, quetiapine, menthol, thujone, lamotigrine, and 3- 
               
               
                   
                 tropanyl indole-3-carboxylate 
               
               
                 HTR4  
                 piboserod, GR-113,808, GR-125,487, RS-39604, SB-203,186, SB-204,070, 
               
               
                 antagonists 
                 and chamomile 
               
               
                 HTR5A  
                 ASP-5736, AS-2030680, AS-2674723, latrepiridine, risperidone, and SB- 
               
               
                 antagonists 
                 699,551 
               
               
                 HTR6  
                 Intepirdine, idalopirdine, cerlapirdine, PF-05212377, amitriptyline, amoxapine, 
               
               
                 antagonists 
                 aripiprazole, asenapine, chlorpromazine, clozapine, dimethyltryptamine, 
               
               
                   
                 doxepin, ergoloid mesylate, iloperidone, imipramine, loxapine, mianserin, 
               
               
                   
                 nortriptyline, olanzapine, quetiapine, sertindole, SGS518, tiapride, 
               
               
                   
                 ziprasidone, CHEMBL3799529, CHEMBL1922614, CHEMBL2012643, 
               
               
                   
                 CHEMBL60264, CHEMBL2407547, CHEMBL2407553, CHEMBL2407545, 
               
               
                   
                 CHEMBL1412853, CHEMBL605938, CHEMBL2407551, CHEMBL2414725, 
               
               
                   
                 CHEMBL3398396, CHEMBL2012637, CHEMBL184165, CHEMBL593889, 
               
               
                   
                 CHEMBL3121422, CHEMBL2414704, CHEMBL2012637, CHEMBL595301, 
               
               
                   
                 CHEMBL2414711, CHEMBL577570, CHEMBL574403, CHEMBL574856, 
               
               
                   
                 CHEMBL575270, CHEMBL573521, CHEMBL574625, CHEMBL575310, 
               
               
                   
                 CHEMBL578631, CHEMBL573981, CHEMBL576967, CHEMBL2414732, 
               
               
                   
                 CHEMBL3398394, CHEMBL3398395, CHEMBL3398389, CHEMBL185115, 
               
               
                   
                 CHEMBL585169, CHEMBL3262393, CHEMBL3398392, CHEMBL605292, 
               
               
                   
                 CHEMBL2414713, CHEMBL606869, CHEMBL3398397, CHEMBL2414726, 
               
               
                   
                 CHEMBL3262432, CHEMBL2407540,  
               
               
                   
                 CHEMBL3398398, CHEMBL2407562, CHEMBL2414705, 
               
               
                   
                 CHEMBL2414707, CHEMBL2012646, CHEMBL610252, 
               
               
                   
                 CHEMBL178561, CHEMBL3398390, CHEMBL2407549, CHEMBL2407542, 
               
               
                   
                 CHEMBL3398391, CHEMBL3823832, CHEMBL605738, CHEMBL2414712, 
               
               
                   
                 CHEMBL183629, CHEMBL2414722, CHEMBL2012639, CHEMBL2047561, 
               
               
                   
                 CHEMBL2414728, CHEMBL3094320, CHEMBL2407555,  
               
               
                   
                 CHEMBL2012639, CHEMBL3094311, 
               
               
                   
                 ALX-1161, AVN-211, BVT-5182, BVT-74316, ALX-1161, 
               
               
                   
                 AVN-211, BVT-5182, BVT-74316, cerlapiridine, EGIS-12233, idalopiridine, 
               
               
                   
                 interpridine, latrepiridine, MS-245, PRX-07034, SB-258,585, SB-271,046, SB- 
               
               
                   
                 357,134, SB-339,885, Ro 04-6790, Ro-4368554, sertindole, olanzapine, 
               
               
                   
                 asenapine, clozapine, rosa rugosa extract, and WAY-255315 
               
               
                 HTR7  
                 CHEMBL39, CHEMBL260907, CHEMBL258785, CHEMBL428781, 
               
               
                 antagonists 
                 CHEMBL261231, CHEMBL408717, CHEMBL260756, CHEMBL436700, 
               
               
                   
                 CHEMBL259001, CHEMBL259199, CHEMBL261434, CHEMBL260022, 
               
               
                   
                 CHEMBL3310123, CHEMBL2392349, CHEMBL260906, CHEMBL261102, 
               
               
                   
                 CHEMBL409156, CHEMBL260705, CHEMBL258995, CHEMBL261019, 
               
               
                   
                 CHEMBL261291, CHEMBL258956, CHEMBL407411, CHEMBL2392351, 
               
               
                   
                 CHEMBL2035283, CHEMBL2035278, CHEMBL2035281,  
               
               
                   
                 CHEMBL2034985, CHEMBL2035277, CHEMBL2035280,  
               
               
                   
                 CHEMBL2035282, CHEMBL2035276, CHEMBL2035275,  
               
               
                   
                 CHEMBL2035274, CHEMBL2035279, CHEMBL260073, 
               
               
                   
                 CHEMBL260514, CHEMBL259776, CHEMBL260706, CHEMBL259407, 
               
               
                   
                 CHEMBL259827, CHEMBL261149, CHEMBL405892, CHEMBL260902, 
               
               
                   
                 CHEMBL260804, CHEMBL411104, CHEMBL407966, CHEMBL261573, 
               
               
                   
                 CHEMBL258525, CHEMBL409358, CHEMBL260648, CHEMBL260029, 
               
               
                   
                 CHEMBL409157, CHEMBL259415, CHEMBL261572, CHEMBL261151, 
               
               
                   
                 CHEMBL410042, CHEMBL261337, CHEMBL260903, CHEMBL261433, 
               
               
                   
                 CHEMBL412153, CHEMBL260249, CHEMBL420863, CHEMBL259619, 
               
               
                   
                 CHEMBL259414, CHEMBL260023, CHEMBL325516, CHEMBL260250, 
               
               
                   
                 CHEMBL114379, CHEMBL260971, CHEMBL261187, CHEMBL114484, 
               
               
                   
                 CHEMBL410043, CHEMBL410075, CHEMBL261099, CHEMBL116463, 
               
               
                   
                 CHEMBL198949, CHEMBL411442, CHEMBL411868, CHEMBL260901, 
               
               
                   
                 CHEMBL116735, CHEMBL260969, CHEMBL258524, CHEMBL259625, 
               
               
                   
                 CHEMBL115249, CHEMBL326263, CHEMBL410722, CHEMBL267615, 
               
               
                   
                 CHEMBL261232, CHEMBL113956, CHEMBL117537, CHEMBL260003, 
               
               
                   
                 CHEMBL261100, CHEMBL409107, CHEMBL364005, CHEMBL115229, 
               
               
                   
                 CHEMBL262589, CHEMBL194305, CHEMBL1785074, CHEMBL1784916, 
               
               
                   
                 CHEMBL3545220, amisulpride, amitriptyline, amoxapine, clomipramine, 
               
               
                   
                 clozapine, DR-4485, fluphenazine, fluperlapine, ICI 169,369, imipramine, 
               
               
                   
                 ketanserine, JNJ-18038683, loxapine, lurasidone, LY-215,840, maprotiline, 
               
               
                   
                 methysergide, mesulergine, mianserin, olanzepine, pimozide, ritanserin, SB- 
               
               
                   
                 258,719, SB-258,741, SB-269,970, SB-656,104-A, SB-691,673, sertindole, 
               
               
                   
                 spiperone, tenilapine, TFMPP, vortioxetine, trifluoperazine, ziprasidone, and 
               
               
                   
                 zotepine 
               
               
                   
               
            
           
         
       
     
                     TABLE 3                  SEROTONIN RECEPTOR SIGNALING INHIBITORS                     Signaling            protein           or pathway   Inhibitors               beta arrestin   CHEMBL1718737, CHEMBL1524916, CHEMBL1972037, CHEMBL1446929,       signaling   CHEMBL1700996, CHEMBL1307207, CHEMBL1508982, CHEMBL51085,           CHEMBL1407756, CHEMBL1464853, CHEMBL1706454, CHEMBL131037,           CHEMBL466853, CHEMBL1336052, CHEMBL278037, CHEMBL1570587,           CHEMBL1489368, CHEMBL1405652       ERK1,    FR180204, FR148083, SCH772984, BVD-523 (ulixertinib), LY3214996,       ERK2   MK8353, BVD-0994, GDC-0994, VTX11e, SC1, DEL-22379       MAPK   JNK 1-3 inhibitors (e.g., SP600125, JNK-IN-8, CC-930 (Tanzisertib), JNK           inhibitor IX, BI-78D3, Anisomycin, AS601245, AS602801 (Bentamapimod,           PGL5001), AEG 3482, CC-401, SP600125, SU 3327, D-JNKI-1 (XG-102, AM-           111), TI-JIP, TAT-TIJIP, L-JNKI (XG-101), CEP-1347 (KT7515), Semapimod (CNI-           1493), BI78D3, BI87G9), p38 MAPK inhibitors (e.g., SB203580, Doramapimod           (BIRB 796), SB202190 (FHPI), LY2228820, VX-702, Pamapimod (R-1503,           Ro4402257), PH-797804, VX-745, TAK-715, SB239063, Skepinone-L,           Losmapimod (GW856553X), BMS-582949, Pexmetinib (ARRY-614), SCIO-469,           SD-0006, AMG-548, SB-681323, LY3007113, trolox, MW181, ginsenoside Rg1,           RWJ 67657), and Erk5 inhibitors (e.g., XMD8-92, ERK5-IN-1, DEL-22379, BIX           02189, TG02, AX15836, AX15839, AX15892, AX15910, XMD17-109)                    
Agent Modalities
 
     A serotonin receptor inhibitor can be selected from a number of different modalities. A serotonin receptor inhibitor can be a small molecule (e.g., a small molecule serotonin receptor antagonist, an inhibitor of a signaling cascade, or an epigenetic modifier), a nucleic acid molecule (e.g., DNA molecule or RNA molecule, e.g., mRNA or inhibitory RNA molecule (e.g., siRNA, shRNA, or miRNA), or a hybrid DNA-RNA molecule), or a polypeptide (e.g., an antibody molecule, e.g., an antibody or antigen binding fragment thereof). A serotonin receptor inhibitor can also be a viral vector expressing a serotonin receptor inhibitor (e.g., a viral vector expressing a neurotoxin) or a cell infected with a viral vector. Any of these modalities can be a serotonin receptor inhibitor directed to target (e.g., to reduce or inhibit) serotonin receptor function, serotonin receptor expression, or serotonin receptor signaling. 
     The small molecule, peptide, polypeptide, or antibody molecule can be modified. For example, the modification can be a chemical modification, e.g., conjugation to a marker, e.g., fluorescent marker or a radioactive marker. In other examples, the modification can include conjugation to a molecule that enhances the stability or half-life of the serotonin receptor inhibitor (e.g., an Fc domain of an antibody or serum albumin, e.g., human serum albumin). The modification can also include conjugation to an antibody to target the agent to a particular cell or tissue. Additionally, the modification can be a chemical modification, packaging modification (e.g., packaging within a nanoparticle or microparticle), or targeting modification to prevent the agent from crossing the blood brain barrier. 
     Small Molecules 
     Numerous small molecule serotonin receptor inhibitors useful in the methods of the invention are described herein and additional small molecule serotonin receptor inhibitors useful as therapies for cancer can also be identified through screening based on their ability to reduce or inhibit serotonin receptor function or signaling. Exemplary small molecule inhibitors (e.g., antagonists) for use in the methods and compositions described herein are listed in Table 2. 
     Small molecules include, but are not limited to, small peptides, peptidomimetics (e.g., peptoids), amino acids, amino acid analogs, synthetic polynucleotides, polynucleotide analogs, nucleotides, nucleotide analogs, organic and inorganic compounds (including heterorganic and organometallic compounds) generally having a molecular weight less than about 5,000 grams per mole, e.g., organic or inorganic compounds having a molecular weight less than about 2,000 grams per mole, e.g., organic or inorganic compounds having a molecular weight less than about 1,000 grams per mole, e.g., organic or inorganic compounds having a molecular weight less than about 500 grams per mole, and salts, esters, and other pharmaceutically acceptable forms of such compounds. 
     In some embodiments, the serotonin receptor inhibitor is a small molecule inhibitor (e.g., antagonist) listed in Table 2. Serotonin receptor inhibitors (e.g., antagonists) can be used to treat a disorder or condition described herein. A pharmaceutical composition including the serotonin receptor inhibitor (e.g., antagonist) can be formulated for treatment of a cancer described herein. In some embodiments, a pharmaceutical composition that includes the serotonin receptor inhibitor (e.g., antagonist) is formulated for local administration, e.g., to the affected site in a subject. 
     Antibodies 
     The serotonin receptor inhibitor can be an antibody or antigen binding fragment thereof. For example, a serotonin receptor inhibitor described herein is an antibody that reduces or blocks the activity and/or function of a serotonin receptor through binding to serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). 
     The making and use of therapeutic antibodies against a target antigen (e.g., against a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7) is known in the art. See, for example, the references cited herein above, as well as Zhiqiang An (Editor), Therapeutic Monoclonal Antibodies: From Bench to Clinic. 1st Edition. Wiley 2009, and also Greenfield (Ed.), Antibodies: A Laboratory Manual. (Second edition) Cold Spring Harbor Laboratory Press 2013, for methods of making recombinant antibodies, including antibody engineering, use of degenerate oligonucleotides, 5′-RACE, phage display, and mutagenesis; antibody testing and characterization; antibody pharmacokinetics and pharmacodynamics; antibody purification and storage; and screening and labeling techniques. 
     Nucleic Acids 
     Inhibitory RNA 
     In some embodiments, the serotonin receptor inhibitor is an inhibitory RNA molecule, e.g., that acts by way of the RNA interference (RNAi) pathway. An inhibitory RNA molecule can decrease the expression level (e.g., protein level or mRNA level) of a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). For example, an inhibitory RNA molecule includes a short interfering RNA, short hairpin RNA, and/or a microRNA that targets a full-length a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). A siRNA is a double-stranded RNA molecule that typically has a length of about 19-25 base pairs. A shRNA is a RNA molecule including a hairpin turn that decreases expression of target genes via RNAi. shRNAs can be delivered to cells in the form of plasmids, e.g., viral or bacterial vectors, e.g., by transfection, electroporation, or transduction). A microRNA is a non-coding RNA molecule that typically has a length of about 22 nucleotides. MiRNAs bind to target sites on mRNA molecules and silence the mRNA, e.g., by causing cleavage of the mRNA, destabilization of the mRNA, or inhibition of translation of the mRNA. In embodiments, the inhibitory RNA molecule decreases the level and/or activity of a negative regulator of function or a positive regulator of function. In other embodiments, the inhibitory RNA molecule decreases the level and/or activity of an inhibitor of a positive regulator of function. 
     An inhibitory RNA molecule can be modified, e.g., to contain modified nucleotides, e.g., 2′-fluoro, 2′-o-methyl, 2′-deoxy, unlocked nucleic acid, 2′-hydroxy, phosphorothioate, 2′-thiouridine, 4′-thiouridine, 2′-deoxyuridine. Without being bound by theory, it is believed that certain modification can increase nuclease resistance and/or serum stability, or decrease immunogenicity. 
     In some embodiments, the inhibitory RNA molecule decreases the level and/or activity or function of a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). In embodiments, the inhibitory RNA molecule inhibits expression of a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). In other embodiments, the inhibitor RNA molecule increases degradation of a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7) and/or decreases the stability (i.e., half-life) of a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). The inhibitory RNA molecule can be chemically synthesized or transcribed in vitro. 
     The making and use of inhibitory therapeutic agents based on non-coding RNA such as ribozymes, RNAse P, siRNAs, and miRNAs are also known in the art, for example, as described in Sioud, RNA Therapeutics: Function, Design, and Delivery (Methods in Molecular Biology). Humana Press 2010. 
     Gene Editing 
     In some embodiments, the serotonin receptor inhibitor is a component of a gene editing system. For example, the serotonin receptor inhibitor introduces an alteration (e.g., insertion, deletion (e.g., knockout), translocation, inversion, single point mutation, or other mutation) in a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). Exemplary gene editing systems include the zinc finger nucleases (ZFNs), Transcription Activator-Like Effector-based Nucleases (TALEN), and the clustered regulatory interspaced short palindromic repeat (CRISPR) system. ZFNs, TALENs, and CRISPR-based methods are described, e.g., in Gaj et al. Trends Biotechnol. 31.7(2013):397-405. 
     CRISPR refers to a set of (or system including a set of) clustered regularly interspaced short palindromic repeats. A CRISPR system refers to a system derived from CRISPR and Cas (a CRISPR-associated protein) or other nuclease that can be used to silence or mutate a gene described herein. The CRISPR system is a naturally occurring system found in bacterial and archaeal genomes. The CRISPR locus is made up of alternating repeat and spacer sequences. In naturally-occurring CRISPR systems, the spacers are typically sequences that are foreign to the bacterium (e.g., plasmid or phage sequences). The CRISPR system has been modified for use in gene editing (e.g., changing, silencing, and/or enhancing certain genes) in eukaryotes. See, e.g., Wiedenheft et al., Nature 482: 331, 2012. For example, such modification of the system includes introducing into a eukaryotic cell a plasmid containing a specifically-designed CRISPR and one or more appropriate Cas proteins. The CRISPR locus is transcribed into RNA and processed by Cas proteins into small RNAs that include a repeat sequence flanked by a spacer. The RNAs serve as guides to direct Cas proteins to silence specific DNA/RNA sequences, depending on the spacer sequence. See, e.g., Horvath et al., Science 327: 167, 2010; Makarova et al., Biology Direct 1:7, 2006; Pennisi, Science 341: 833, 2013. In some examples, the CRISPR system includes the Cas9 protein, a nuclease that cuts on both strands of the DNA. See, e.g., Id. 
     In some embodiments, in a CRISPR system for use described herein, e.g., in accordance with one or more methods described herein, the spacers of the CRISPR are derived from a target gene sequence, e.g., from a serotonin receptor sequence (e.g., a sequence of a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). 
     In some embodiments, the serotonin receptor inhibitor includes a guide RNA (gRNA) for use in a clustered regulatory interspaced short palindromic repeat (CRISPR) system for gene editing. In embodiments, the serotonin receptor inhibitor includes a zinc finger nuclease (ZFN), or an mRNA encoding a ZFN, that targets (e.g., cleaves) a nucleic acid sequence (e.g., DNA sequence) of a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). In embodiments, the serotonin receptor inhibitor includes a TALEN, or an mRNA encoding a TALEN, that targets (e.g., cleaves) a nucleic acid sequence (e.g., DNA sequence) of a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). 
     For example, the gRNA can be used in a CRISPR system to engineer an alteration in a gene (e.g., a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). In other examples, the ZFN and/or TALEN can be used to engineer an alteration in a gene (e.g., a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). Exemplary alterations include insertions, deletions (e.g., knockouts), translocations, inversions, single point mutations, or other mutations. The alteration can be introduced in the gene in a cell, e.g., in vitro, ex vivo, or in vivo. In some embodiments, the alteration decreases the level and/or activity of (e.g., knocks down or knocks out) a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7), e.g., the alteration is a negative regulator of function. In yet another example, the alteration corrects a defect (e.g., a mutation causing a defect), in a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). 
     In certain embodiments, the CRISPR system is used to edit (e.g., to add or delete a base pair) a target gene, e.g., a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). In other embodiments, the CRISPR system is used to introduce a premature stop codon, e.g., thereby decreasing the expression of a target gene. In yet other embodiments, the CRISPR system is used to turn off a target gene in a reversible manner, e.g., similarly to RNA interference. In embodiments, the CRISPR system is used to direct Cas to a promoter of a target gene, e.g., a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7) thereby blocking an RNA polymerase sterically. 
     In some embodiments, a CRISPR system can be generated to edit a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7) using technology described in, e.g., U.S. Publication No. 20140068797; Cong, Science 339: 819, 2013; Tsai, Nature Biotechnol., 32:569, 2014; and U.S. Pat. Nos. 8,871,445; 8,865,406; 8,795,965; 8,771,945; and 8,697,359. 
     In some embodiments, the CRISPR interference (CRISPRi) technique can be used for transcriptional repression of specific genes, e.g., the gene encoding a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). In CRISPRi, an engineered Cas9 protein (e.g., nuclease-null dCas9, or dCas9 fusion protein, e.g., dCas9-KRAB or dCas9-SID4X fusion) can pair with a sequence specific guide RNA (sgRNA). The Cas9-g RNA complex can block RNA polymerase, thereby interfering with transcription elongation. The complex can also block transcription initiation by interfering with transcription factor binding. The CRISPRi method is specific with minimal off-target effects and is multiplexable, e.g., can simultaneously repress more than one gene (e.g., using multiple gRNAs). Also, the CRISPRi method permits reversible gene repression. 
     In some embodiments, CRISPR-mediated gene activation (CRISPRa) can be used for transcriptional activation, e.g., of one or more genes described herein, e.g., a gene that inhibits a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). In the CRISPRa technique, dCas9 fusion proteins recruit transcriptional activators. For example, dCas9 can be used to recruit polypeptides (e.g., activation domains) such as VP64 or the p65 activation domain (p65D) and used with sgRNA (e.g., a single sgRNA or multiple sgRNAs), to activate a gene or genes, e.g., endogenous gene(s). Multiple activators can be recruited by using multiple sgRNAs—this can increase activation efficiency. A variety of activation domains and single or multiple activation domains can be used. In addition to engineering dCas9 to recruit activators, sgRNAs can also be engineered to recruit activators. For example, RNA aptamers can be incorporated into a sgRNA to recruit proteins (e.g., activation domains) such as VP64. In some examples, the synergistic activation mediator (SAM) system can be used for transcriptional activation. In SAM, MS2 aptamers are added to the sgRNA. MS2 recruits the MS2 coat protein (MCP) fused to p65AD and heat shock factor 1 (HSF1). The CRISPRi and CRISPRa techniques are described in greater detail, e.g., in Dominguez et al., Nat. Rev. Mol. Cell Biol. 17:5, 2016, incorporated herein by reference. 
     Viral Vectors 
     The serotonin receptor inhibitor can be delivered by a viral vector (e.g., a viral vector expressing an inhibitory RNA directed to a serotonin receptor or a neurotoxin). A viral vector may be administered to a cell or to a subject (e.g., a human subject or animal model). A viral vector expressing an inhibitory RNA directed to a serotonin receptor (e.g., a serotonin receptor listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7) or neurotoxin from Table 13 or DON or pertussis toxin can be administered to a cell or to a subject (e.g., a human subject or animal model) to decrease or block serotonergic neurotransmission. Viral vectors can be directly administered (e.g., injected) to a tumor containing immune cells or to an immune cell to treat cancer. 
     Viral genomes provide a rich source of vectors that can be used for the efficient delivery of exogenous genes into a mammalian cell. Viral genomes are particularly useful vectors for gene delivery because the polynucleotides contained within such genomes are typically incorporated into the nuclear genome of a mammalian cell by generalized or specialized transduction. These processes occur as part of the natural viral replication cycle, and do not require added proteins or reagents in order to induce gene integration. Examples of viral vectors include a retrovirus (e.g., Retroviridae family viral vector), adenovirus (e.g., Ad5, Ad26, Ad34, Ad35, and Ad48), parvovirus (e.g., adeno-associated viruses), coronavirus, negative strand RNA viruses such as orthomyxovirus (e.g., influenza virus), rhabdovirus (e.g., rabies and vesicular stomatitis virus), paramyxovirus (e.g., measles and Sendai), positive strand RNA viruses, such as picornavirus and alphavirus, and double stranded DNA viruses including adenovirus, herpesvirus (e.g., Herpes Simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus, replication deficient herpes virus), and poxvirus (e.g., vaccinia, modified vaccinia Ankara (MVA), fowlpox and canarypox). Other viruses include Norwalk virus, togavirus, flavivirus, reoviruses, papovavirus, hepadnavirus, human papilloma virus, human foamy virus, and hepatitis virus, for example. Examples of retroviruses include: avian leukosis-sarcoma, avian C-type viruses, mammalian C-type, B-type viruses, D-type viruses, oncoretroviruses, HTLV-BLV group, lentivirus, alpharetrovirus, gammaretrovirus, spumavirus (Coffin, J. M., Retroviridae: The viruses and their replication, Virology (Third Edition) Lippincott-Raven, Philadelphia, 1996). Other examples include murine leukemia viruses, murine sarcoma viruses, mouse mammary tumor virus, bovine leukemia virus, feline leukemia virus, feline sarcoma virus, avian leukemia virus, human T-cell leukemia virus, baboon endogenous virus, Gibbon ape leukemia virus, Mason Pfizer monkey virus, simian immunodeficiency virus, simian sarcoma virus, Rous sarcoma virus and lentiviruses. Other examples of vectors are described, for example, in U.S. Pat. No. 5,801,030, the teachings of which are incorporated herein by reference. 
     Cell-Based Therapies 
     A serotonin receptor inhibitor described herein can be administered to a cell in vitro (e.g., an immune cell), which can subsequently be administered to a subject (e.g., a human subject or animal model). The serotonin receptor inhibitor can be administered to the cell to affect an immune response (e.g., activation, polarization, antigen presentation, cytokine production, migration, proliferation, or differentiation) as described herein. Once the immune response is elicited, the cell can be administered to a subject (e.g., injected) to treat cancer. The immune cell can be locally administered (e.g., injected into a tumor, lymph node, or secondary lymphoid organ). 
     A serotonin receptor inhibitor can also be administered to a cell in vitro (e.g., an immune cell) to alter gene or protein expression in the cell. The serotonin receptor inhibitor can decrease the expression of serotonin receptor in an immune cell. The serotonin receptor inhibitor can be a polypeptide or nucleic acid (e.g., inhibitory RNA) described above. The serotonin receptor inhibitor can be an exogenous gene encoded by a plasmid that is introduced into the cell using standard methods (e.g., calcium phosphate precipitation, electroporation, microinjection, infection, lipofection, impalefection, laserfection, or magnetofection). The serotonin receptor inhibitor can be a viral vector (e.g., a viral vector expressing a serotonin receptor inhibitor, e.g., an inhibitory RNA or neurotoxin) that is introduced to the cell using standard transduction methods. The plasmid or vector can also contain a reporter construct (e.g., a fluorescent reporter) that can be used to confirm expression of the transgene by the immune cell. After the immune cell has been contacted with a serotonin receptor inhibitor to or decrease gene or protein expression or reduce or inhibit serotonin receptor activity, the cell can be administered to a subject (e.g., injected) to treat cancer. The immune cell can be locally administered (e.g., injected into a tumor, lymph node, or secondary lymphoid organ). 
     The cell can be administered to a subject immediately after being contacted with a serotonin receptor inhibitor (e.g., within 5, 10, 15, 30, 45, or 60 minutes of being contacted with a serotonin receptor inhibitor), or 6 hours, 12 hours, 24 hours, 2 days, 3, days, 4 days, 5, days, 6 days, 7 days or more after being contacted with a serotonin receptor inhibitor. The method can include an additional step of evaluating the immune cell for an immune cell activity (e.g., activation, polarization, antigen presentation, cytokine production, migration, proliferation, or differentiation) or modulation of gene or protein expression after contact with a serotonin receptor inhibitor and before administration to a subject. 
     Blood Brain Barrier Permeability 
     In some embodiments, the serotonin receptor inhibitors for use in the present invention are agents that are not capable of crossing, or that do not cross, the blood brain barrier (BBB) of a mammal, e.g., an experimental rodent (e.g., mouse or rat), dog, pig, non-human primate, or a human. The BBB is a highly selective semipermeable membrane barrier that separates the circulating blood from the brain extracellular fluid (e.g., cerebrospinal fluid) in the central nervous system (CNS). The BBB is made up of high-density endothelial cells, which are connected by tight junctions. These cells prevent most molecular compounds in the bloodstream (e.g., large molecules and hydrophilic molecules) from entering the brain. Water, some gases (e.g., oxygen and carbon dioxide), and lipid-soluble molecules (e.g., hydrophobic molecules, such as steroid hormones) can cross the BBB by passive diffusion. Molecules that are needed for neural function, such as glucose and amino acids, are actively transported across the BBB. 
     A number of approaches can be used to render an agent BBB impermeable. These methods include modifications to increase an agent&#39;s size, polarity, or flexibility or reduce its lipophilicity, targeting approaches to direct an agent to another part of the body and away from the brain, and packaging approaches to deliver an agent in a form that does not freely diffuse across the BBB. These approaches can be used to render a BBB permeable serotonin receptor inhibitor impermeable, and they can also be used to improve the properties (e.g., cell-specific targeting) of a serotonin receptor inhibitor that does not cross the BBB. The methods that can be used to render an agent BBB impermeable are discussed in greater detail herein below. 
     Formulation of BBB-Impermeable Agents for Enhanced Cell Targeting 
     One approach that can be used to render a serotonin receptor inhibitor BBB impermeable is to conjugate the agent to a targeting moiety that directs it somewhere other than the brain. The targeting moiety can be an antibody for a receptor expressed by the target cell (e.g., N-Acetylgalactosamine for liver transport; DGCR2, GBF1, GPR44 or SerpinB10 for pancreas transport; Secretoglobin, family 1A, member 1 for lung transport). The targeting moiety can also be a ligand of any receptor or other molecular identifier expressed on the target cell in the periphery. These targeting moieties can direct the serotonin receptor inhibitor of interest to its corresponding target cell, and can also prevent BBB crossing by directing the agent away from the BBB and increasing the size of the serotonin receptor inhibitor via conjugation of the targeting moiety. 
     Serotonin receptor inhibitors can also be rendered BBB impermeable through formulation in a particulate delivery system (e.g., a nanoparticle, liposome, or microparticle), such that the agent is not freely diffusible in blood and cannot cross the BBB. The particulate formulation used can be chosen based on the desired localization of the serotonin receptor inhibitor (e.g., a tumor, lymph node, lymphoid organ, or site of inflammation), as particles of different sizes accumulate in different locations. For example, nanoparticles with a diameter of 45 nm or less enter the lymph node, while 100 nm nanoparticles exhibit poor lymph node trafficking. Some examples of the link between particle size and localization in vivo are described in Reddy et al., J Controlled Release 112:26 2006, and Reddy et al., Nature Biotechnology 25:1159 2007. 
     Serotonin receptor inhibitors can be tested after the addition of a targeting moiety or after formulation in a particulate delivery system to determine whether or not they cross the BBB. Models for assessing BBB permeability include in vitro models (e.g., monolayer models, co-culture models, dynamic models, multi-fluidic models, isolated brain microvessels), in vivo models, and computational models as described in He et al., Stroke 45:2514 2014; Bickel, NeuroRx 2:15 2005; and Wang et al., Int J Pharm 288:349 2005. A serotonin receptor inhibitor that exhibits BBB impermeability can be used in the methods described herein. 
     Modification of Existing Compounds to Render them BBB Impermeable 
     There are multiple parameters that have been empirically derived in the field of medicinal chemistry to predict whether a compound will cross the BBB. The most common numeric value for describing permeability across the BBB is the logBB, defined as the logarithmic ratio of the concentration of a compound in the brain and in the blood. Empirical rules of thumb have been developed to predict BBB permeability, including rules regarding molecular size, polar surface area, sum of oxygen and nitrogen atoms, lipophilicity (e.g., partition coefficient between apolar solvent and water), “lipoaffinity”, molecular flexibility, and number of rotatable bonds (summarized in Muehlbacher et al., J Comput Aided Mol Des. 25: 1095 2011; and Geldenhuys et al., Ther Deliv. 6: 961 2015). Some preferred limits on various parameters for BBB permeability are listed in Table 1 of Ghose et al., ACS Chem Neurosci. 3: 50 2012, which is incorporated herein by reference. Based on the parameters shown in the table, one of skill in the art could modify an existing serotonin receptor inhibitor to render it BBB impermeable. 
     One method of modifying a serotonin receptor inhibitor to prevent BBB crossing is to add a molecular adduct that does not affect the target binding specificity, kinetics, or thermodynamics of the agent. Molecular adducts that can be used to render an agent BBB impermeable include polyethylene glycol (PEG), a carbohydrate monomer or polymer, a dendrimer, a polypeptide, a charged ion, a hydrophilic group, deuterium, and fluorine. Serotonin receptor inhibitors can be tested after the addition of one or more molecular adducts or after any other properties are altered to determine whether or not they cross the BBB. Models for assessing BBB permeability include in vitro models (e.g., monolayer models, co-culture models, dynamic models, multi-fluidic models, isolated brain microvessels), in vivo models, and computational models as described in He et al., Stroke 45:2514 2014; Bickel, NeuroRx 2:15 2005; and Wang et al., Int J Pharm 288:349 2005. A serotonin receptor inhibitor that exhibits BBB impermeability can be used in the methods described herein. 
     Screening for or Development of BBB Impermeable Agents 
     Another option for developing BBB impermeable agents is to find or develop new agents that do not cross the BBB. One method for finding new BBB impermeable agents is to screen for compounds that are BBB impermeable. Compound screening can be performed using in vitro models (e.g., monolayer models, co-culture models, dynamic models, multi-fluidic models, isolated brain microvessels), in vivo models, and computational models, as described in He et al., Stroke 45:2514 2014; Bickel, NeuroRx 2:15 2005; Wang et al., Int J Pharm 288:349 2005, and Czupalla et al., Methods Mol Biol 1135:415 2014. For example, the ability of a molecule to cross the blood brain barrier can be determined in vitro using a transwell BBB assay in which microvascular endothelial cells and pericytes are co-cultured separated by a thin macroporous membrane, see e.g., Naik et al., J Pharm Sci 101:1337 2012 and Hanada et al., Int J Mol Sci 15:1812 2014; or in vivo by tracking the brain uptake of the target molecule by histology or radio-detection. Compounds would be deemed appropriate for use as serotonin receptor inhibitors in the methods described herein if they do not display BBB permeability in the aforementioned models. 
     Modulation of Immune Cells 
     The methods described herein can be used to modulate an immune response in a subject or cell by administering to a subject or cell a serotonin receptor inhibitor in a dose (e.g., an effective amount) and for a time sufficient to modulate the immune response. These methods can be used to treat a subject in need of modulating an immune response, e.g., a subject with cancer. One way to modulate an immune response is to modulate an immune cell activity. This modulation can occur in vivo (e.g., in a human subject or animal model) or in vitro (e.g., in acutely isolated or cultured cells, such as human cells from a patient, repository, or cell line, or rodent cells). The types of cells that can be modulated include T cells (e.g., peripheral T cells, cytotoxic T cells/CD8+ T cells, T helper cells/CD4+ T cells, memory T cells, regulatory T cells/Tregs, natural killer T cells/NKTs, mucosal associated invariant T cells, and gamma delta T cells), B cells (e.g., memory B cells, plasmablasts, plasma cells, follicular B cells/B-2 cells, marginal zone B cells, B-1 cells, regulatory B cells/Bregs), dendritic cells (e.g., myeloid DCs/conventional DCs, plasmacytoid DCs, or follicular DCs), granulocytes (e.g., eosinophils, mast cells, neutrophils, and basophils), monocytes, macrophages (e.g., peripheral macrophages or tissue resident macrophages or tumor-resident macrophages), myeloid-derived suppressor cells (MDSCs), NK cells, innate lymphoid cells (ILC1, ILC2, or ILC3), thymocytes, and megakaryocytes. 
     The immune cell activities that can be modulated by administering to a subject or contacting a cell with an effective amount of a serotonin receptor inhibitor described herein include activation (e.g., macrophage, T cell, NK cell, ILC, B cell, dendritic cell, neutrophil, eosinophil, or basophil activation), phagocytosis (e.g., macrophage, neutrophil, monocyte, mast cell, B cell, eosinophil, or dendritic cell phagocytosis), antibody-dependent cellular phagocytosis (e.g., ADCP by monocytes, macrophages, neutrophils, or dendritic cells), antibody-dependent cellular cytotoxicity (e.g., ADCC by NK cells, ILCs, monocytes, macrophages, neutrophils, eosinophils, dendritic cells, or T cells), polarization (e.g., macrophage polarization toward an M1 or M2 phenotype or T cell polarization), proliferation (e.g., proliferation of B cells, T cells, monocytes, macrophages, dendritic cells, NK cells, ILCs, mast cells, neutrophils, eosinophils, or basophils), lymph node homing (e.g., lymph node homing of T cells, B cells, dendritic cells, or macrophages), lymph node egress (e.g., lymph node egress of T cells, B cells, dendritic cells, or macrophages), recruitment (e.g., recruitment of B cells, T cells, monocytes, macrophages, dendritic cells, NK cells, ILCs, mast cells, neutrophils, eosinophils, or basophils), migration (e.g., migration of B cells, T cells, monocytes, macrophages, dendritic cells, NK cells, ILCs, mast cells, neutrophils, eosinophils, or basophils), differentiation (e.g., regulatory T cell differentiation), immune cell cytokine production, antigen presentation (e.g., dendritic cell, macrophage, and B cell antigen presentation), maturation (e.g., dendritic cell maturation), and degranulation (e.g., mast cell, NK cell, ILC, cytotoxic T cell, neutrophil, eosinophil, or basophil degranulation). Innervation of lymph nodes or lymphoid organs, development of high endothelial venules (HEVs), and development of ectopic or tertiary lymphoid organs (TLOs) can also be modulated using the methods described herein. Modulation can increase or decrease these activities, depending on the serotonin receptor inhibitor used to contact the cell or treat a subject. 
     In some embodiments, an effective amount of a serotonin receptor inhibitor is an amount sufficient to modulate (e.g., increase or decrease) one or more (e.g., 2 or more, 3 or more, 4 or more) of the following immune cell activities in the subject or cell: T cell polarization; T cell activation; dendritic cell activation; neutrophil activation; eosinophil activation; basophil activation; T cell proliferation; B cell proliferation; T cell proliferation; monocyte proliferation; macrophage proliferation; dendritic cell proliferation; NK cell proliferation; ILC proliferation; mast cell proliferation; neutrophil proliferation; eosinophil proliferation; basophil proliferation; cytotoxic T cell activation; circulating monocytes; peripheral blood hematopoietic stem cells; macrophage polarization; macrophage phagocytosis; macrophage ADCP, neutrophil phagocytosis; monocyte phagocytosis; mast cell phagocytosis; B cell phagocytosis; eosinophil phagocytosis; dendritic cell phagocytosis; macrophage activation; antigen presentation (e.g., dendritic cell, macrophage, and B cell antigen presentation); antigen presenting cell migration (e.g., dendritic cell, macrophage, and B cell migration); lymph node immune cell homing and cell egress (e.g., lymph node homing and egress of T cells, B cells, dendritic cells, or macrophages); NK cell activation; NK cell ADCC, mast cell degranulation; NK cell degranulation; ILC activation; ILC ADCC; ILC degranulation; cytotoxic T cell degranulation; neutrophil degranulation; eosinophil degranulation; basophil degranulation; neutrophil recruitment; eosinophil recruitment; NKT cell activation; B cell activation; regulatory T cell differentiation; dendritic cell maturation; development of high endothelial venules (HEVs); development of ectopic or tertiary lymphoid organs (TLOs); or lymph node or secondary lymphoid organ innervation. In certain embodiments, the immune response (e.g., an immune cell activity listed herein) is increased in the subject or cell at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 100%, 150%, 200%, 300%, 400%, 500% or more, compared to before the administration. In certain embodiments, the immune response is increased in the subject or cell between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%, between 50-200%, between 100%-500%. 
     After a serotonin receptor inhibitor is administered to treat a patient or contact a cell, a readout can be used to assess the effect on immune cell activity. Immune cell activity can be assessed by measuring a cytokine or marker associated with a particular immune cell type, as listed in Table 4 (e.g., performing an assay listed in Table 4 for the cytokine or marker). In certain embodiments, the parameter is increased in the subject at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 100%, 150%, 200%, 300%, 400%, 500% or more, compared to before the administration. In certain embodiments, the parameter is increased in the subject between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%, between 50-200%, between 100%-500%. A serotonin receptor inhibitor can be administered at a dose (e.g., an effective amount) and for a time sufficient to modulate an immune cell activity described herein below. 
     After a serotonin receptor inhibitor is administered to treat a patient or contact a cell, a readout can be used to assess the effect on immune cell migration. Immune cell migration can be assessed by measuring the number of immune cells in a location of interest (e.g., a lymph node or secondary lymphoid organ, site of inflammation, or a tumor). Immune cell migration can also be assessed by measuring a chemokine, receptor, or marker associated with immune cell migration, as listed in Tables 5 and 6. In certain embodiments, the parameter is increased in the subject at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 100%, 150%, 200%, 300%, 400%, 500% or more, compared to before the administration. In certain embodiments, the parameter is increased in the subject between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%, between 50-200%, between 100%-500%. A serotonin receptor inhibitor can be administered at a dose (e.g., an effective amount) and for a time sufficient to modulate an immune cell migration as described herein below. 
     A serotonin receptor inhibitor described herein can affect immune cell migration. Immune cell migration between peripheral tissues, the blood, and the lymphatic system as well as lymphoid organs is essential for the orchestration of productive innate and adaptive immune responses. Immune cell migration is largely regulated by trafficking molecules including integrins, immunoglobulin cell-adhesion molecules (IgSF CAMs), cadherins, selectins, and a family of small cytokines called chemokines (Table 5). Cell adhesion molecules and chemokines regulate immune cell migration by both inducing extravasation from the circulation into peripheral tissues and acting as guidance cues within peripheral tissues themselves. For extravasation to occur, chemokines must act in concert with multiple trafficking molecules including C-type lectins (L-, P-, and E-selectin), multiple integrins, and cell adhesion molecules (ICAM-1, VCAM-1 and MAdCAM-1) to enable a multi-step cascade of immune cell capturing, rolling, arrest, and transmigration via the blood endothelial barrier (Table 6). Some trafficking molecules are constitutively expressed and manage the migration of immune cells during homeostasis, while others are specifically upregulated by inflammatory processes such as infection, autoimmunity and cancer. 
     The expression of trafficking molecules important for extravasation is mainly regulated on specialized blood vessels called HEVs, which are the entry portals from the circulation into the periphery and are usually present in secondary lymphoid organs (SLOs) and chronically inflamed tissue. Chronically inflamed tissues often develop lymphoid-like structures called TLOs that contain structures resembling SLOs including HEVs, lymphoid stromal cells, and confined compartments of T and B lymphocytes. As they can act as major gateways for immune cell migration into peripheral tissues, TLOs have been shown to be important in the pathogenesis of autoimmune disorders and cancer. 
     Once within peripheral tissues, four modes of immune cell migration have been observed: 1) chemokinesis: migration driven by soluble chemokines, without concentration gradients to provide directional bias, 2) haptokinesis: migration along surfaces presenting immobilized ligands such as chemokines or integrins, without concentration gradients to provide directional bias, 3) chemotaxis: directional migration driven by concentration gradients of soluble chemokines, and 4) haptotaxis: directional migration along surfaces presenting gradients of immobilized ligands such as chemokines or integrins. The response of immune cells to trafficking molecules present on the endothelium depends on the composition, expression, and/or functional activity of their cognate receptors, which in turn depends on activation state and immune cell subtype. 
     Innate immune cells generally migrate toward inflammation-induced trafficking molecules in the periphery. In contrast, naïve T and B cells constantly re-circulate between the blood and secondary lymphoid organs to screen for their cognate antigen presented by activated dendritic cells (DCs) or fibroblastic reticular cells (FRCs), respectively. If activated by recognition of their cognate antigen and appropriate co-stimulation within SLOs, both cell types undergo a series of complex maturation steps, including differentiation and proliferation, ultimately leading to effector and memory immune cell phenotypes. To reach their peripheral target sites, certain effector and memory T and B cell subsets egress from SLOs to the blood circulation via efferent lymphatics. In order to do so, they migrate toward a Sphingosine-1-phosphate (S1P) gradient sensed using their Sphingosine-1-phosphate receptor 1 (S1P 1  or S1 PR1). For successful egress into efferent lymphatics, immune cells need to overcome SLO retention signals through the CCR7/CCL21 axis or through CD69-mediated downregulation of S1 P 1 . 
     Finally, certain immune cell subsets, for example mature dendritic cells (DCs) and memory T cells, migrate from peripheral tissues into SLOs via afferent lymphatics. To exit from peripheral tissues and enter afferent lymphatics, immune cells again largely depend on the CCR7/CCL21 and S1P 1 /S1P axis. Specifically, immune cells need to overcome retention signals delivered via the CCR7/CCL21 axis, and migrate toward an S1P gradient established by the lymphatic endothelial cells using S1P 1 . The selective action of trafficking molecules on distinct immune cell subsets as well as the distinct spatial and temporal expression patterns of both the ligands and receptors are crucial for the fine-tuning of immune responses during homeostasis and disease. 
     Aberrant immune cell migration is observed in multiple immune-related pathologies. Immune cell adhesion deficiencies, caused by molecular defects in integrin expression, fucosylation of selectin ligands, or inside-out activation of integrins on leukocytes and platelets, lead to impaired immune cell migration into peripheral tissues. This results in leukocytosis and in increased susceptibility to recurrent bacterial and fungal infections, which can be difficult to treat and potentially life-threatening. Alternatively, exaggerated migration of specific immune cell subsets into specific peripheral tissues is associated with a multitude of pathologies. For example, excessive neutrophil accumulation in peripheral tissues contributes to the development of ischemia-reperfusion injury, such as that observed during acute myocardial infarction, stroke, shock and acute respiratory distress syndrome. Excessive Th1 inflammation characterized by tissue infiltration of interferon-gamma secreting effector T cells and activated macrophages is associated with atherosclerosis, allograft rejection, hepatitis, and multiple autoimmune diseases including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn&#39;s disease, type 1 diabetes and lupus erythematodes. Excessive Th2 inflammation characterized by tissue infiltration of IL-4, IL-5, and IL-13 secreting Th2 cells, eosinophils and mast cells is associated with asthma, food allergies and atopic dermatitis. 
     In the context of tumor biology, the balance between effector immune cell infiltrates eliminating tumor cells and suppressive immune cell infiltrates protecting tumor cells is critical in determining the net outcome of tumor development, namely elimination, equilibrium, or escape. The main anti-tumor immune cell subsets are NK cells, γδ T cells, Th1 CD4+ and cytotoxic CD8+ T cells (CTLs), mature dendritic cells (mDCs), and inflammatory macrophages (often referred to as M1 macrophages). The main pro-tumor immune cell subsets are suppressive tumor-associated macrophages (TAM, often referred to as M2 macrophages), MDSC, regulatory T cells (Treg), and immature dendritic cells (iDCs). While effector immune cells subsets are generally attracted to migrate into the tumor microenvironment via CXCR3 and its ligands CXCL9, CXCL10 and CXCL11, suppressive immune cell subsets depend on multiple sets of chemokine and chemokine receptors, including CCR2/CCL2, CCR5/CCL5, CXCR1/CXCL8 (IL8), CXCR2/CXCL5, and CXCR4/CXCL12. Accordingly, the upregulation of CXCL9 and CXCL10 within the tumor generally correlates with good prognosis, and upregulation of suppressive chemokines correlates with bad prognosis of cancer patients. 
     Specific chemokine pathways not only increase the infiltration of immunosuppressive immune cell subsets, but also promote tumor angiogenesis and metastasis and are thus interesting targets for the development of anti-cancer therapies. Inducing T cell migration into tumors might be especially beneficial in the context of cancer immunotherapy, as a T-cell inflamed microenvironment correlates with good response to these types of interventions. 
     Finally, tumor-draining lymph nodes (tdLNs) are essential gateways for the induction of adaptive immune responses against tumor cells. However, even though tdLNs are exposed to antigens shed by the upstream tumor cells, they often contain more immunosuppressive cytokines and cells than a non-involved lymph node. This is because a multitude of immunosuppressive molecules are secreted by the upstream tumor microenvironment, thus influencing the immune status of the downstream lymph node. Therefore, strategies that could alter immune cell migration into the tumor-draining lymph node could shift the balance between suppressive and effector immune cells in favor of the latter, thus unleashing potent anti-tumor immune responses. 
     In some embodiments, a serotonin receptor inhibitor described herein increases development of HEVs or TLOs. In some embodiments, a serotonin receptor inhibitor described herein increases one or more of monocyte migration, monocyte proliferation, monocyte recruitment, monocyte tumor homing, monocyte differentiation, monocyte activation, monocyte degranulation, monocyte ADCP, monocyte ADCC, monocyte polarization toward an inflammatory phenotype, monocyte antigen presentation, or monocyte production of pro-inflammatory cytokines (e.g., IL-8). In some embodiments, a serotonin receptor inhibitor described herein decreases monocyte tumor egress and/or monocyte expression of one or more serotonin receptors (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). 
     In some embodiments, a serotonin receptor inhibitor described herein increases one or more of macrophage migration, macrophage proliferation, macrophage recruitment, macrophage tumor homing, macrophage differentiation, macrophage activation, macrophage polarization toward an inflammatory phenotype (e.g., polarization toward an M1 phenotype, e.g., polarization of an M2 macrophage toward an M1 phenotype), macrophage antigen presentation, macrophage degranulation, macrophage ADCC, macrophage production of pro-inflammatory cytokines (e.g., IL-8), or macrophage ADCP. In some embodiments, a serotonin receptor inhibitor described herein decreases macrophage tumor egress and/or macrophage expression of one or more serotonin receptors (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7). In some embodiments, the macrophage is an M2 macrophage. 
     In some embodiments, a serotonin receptor inhibitor described herein increases one or more of myeloid derived suppressor cell (MDSC) migration, MDSC proliferation, MDSC recruitment, MDSC tumor homing, MDSC differentiation, MDSC activation, MDSC polarization toward an inflammatory phenotype, MDSC antigen presentation, MDSC ADCC, MDSC degranulation, MDSC production of pro-inflammatory cytokines (e.g., IL-8), or MDSC ADCP. In some embodiments, a serotonin receptor inhibitor described herein decreases MDSC tumor egress and/or MDSC expression of one or more serotonin receptors (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7). 
     In some embodiments, a serotonin receptor inhibitor described herein increases one or more of T cell migration, T cell proliferation, T cell recruitment, T cell tumor homing, T cell differentiation, T cell activation, T cell polarization toward an inflammatory phenotype, T cell antigen presentation, T cell ADCC, T cell degranulation, T cell production of pro-inflammatory cytokines (e.g., IL-8), or T cell ADCP. In some embodiments, a serotonin receptor inhibitor described herein decreases T cell tumor egress and/or T cell expression of one or more serotonin receptors (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7). 
     In some embodiments, a serotonin receptor inhibitor described herein increases one or more of dendritic cell migration, dendritic cell proliferation, dendritic cell recruitment, dendritic cell tumor homing, dendritic cell differentiation, dendritic cell activation, dendritic cell polarization toward an inflammatory phenotype, dendritic cell antigen presentation, dendritic cell ADCC, dendritic cell degranulation, dendritic cell production of pro-inflammatory cytokines (e.g., IL-8), or dendritic cell ADCP. In some embodiments, a serotonin receptor inhibitor described herein decreases dendritic cell tumor egress and/or dendritic cell expression of one or more serotonin receptors (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7). 
     In some embodiments, a serotonin receptor inhibitor described herein increases one or more of neutrophil migration, neutrophil proliferation, neutrophil recruitment, neutrophil tumor homing, or neutrophil activation. In some embodiments, a serotonin receptor inhibitor described herein increases one or more of neutrophil differentiation, neutrophil polarization toward an inflammatory phenotype, neutrophil degranulation, neutrophil ADCC, neutrophil antigen presentation, or neutrophil production of pro-inflammatory cytokines (e.g., IL-8), or neutrophil ADCP. In some embodiments, a serotonin receptor inhibitor described herein decreases neutrophil tumor egress and/or neutrophil expression of one or more serotonin receptors (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7). In some embodiments, a serotonin receptor inhibitor described herein increases one or more of neutrophil migration, neutrophil activation, neutrophil recruitment, or neutrophil tumor homing by increasing IL-8 cytokine production by T cells, dendritic cells, macrophages, monocytes, or MDSCs, or by increasing activation or polarization of T cells, dendritic cells, macrophages, monocytes, or MDSCs. 
     Immune Effects 
     A variety of in vitro and in vivo assays can be used to determine how a serotonin receptor inhibitor affects an immune cell activity. The effect of a serotonin receptor inhibitor on T cell polarization in a subject can be assessed by evaluation of cell surface markers on T cells obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and T cells from the sample evaluated for one or more (e.g., 2, 3, or 4 or more) Th1-specific markers: T-bet, IL-12R, STAT4, or chemokine receptors CCR5, CXCR6, and CXCR3; or Th2-specific markers: CCR3, CXCR4, or IL-4Ra. T cell polarization can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to T cells in vitro (e.g., T cells obtained from a subject, animal model, repository, or commercial source) and measuring the aforementioned markers to evaluate T cell polarization. These markers can be assessed using flow cytometry, immunohistochemistry, in situ hybridization, and other assays that allow for measurement of cellular markers. Comparing results from before and after administration of a serotonin receptor inhibitor can be used to determine its effect. 
     The effect of a serotonin receptor inhibitor on T cell activation in a subject can be assessed by evaluation of cellular markers on T cells obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and T cells from the sample evaluated for one or more (e.g., 2, 3, 4 or more) activation markers: CD25, CD71, CD26, CD27, CD28, CD30, CD154, CD40L, CD134, CD69, CD62L or CD44. T cell activation can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to T cells in vitro (e.g., T cells obtained from a subject, animal model, repository, or commercial source) and measuring the aforementioned markers to evaluate T cell activation. Similar approaches can be used to assess the effect of a serotonin receptor inhibitor on activation of other immune cells, such as eosinophils (markers: CD35, CD11b, CD66, CD69 and CD81), dendritic cells (makers: IL-8, MHC class II, CD40, CD80, CD83, and CD86), basophils (CD63, CD13, CD4, and CD203c), ILCs (markers: CD69), and neutrophils (CD11b, CD35, CD66b and CD63). These markers can be assessed using flow cytometry, immunohistochemistry, in situ hybridization, and other assays that allow for measurement of cellular markers. Comparing results from before and after administration of a serotonin receptor inhibitor can be used to determine its effect. 
     The effect of a serotonin receptor inhibitor on immune cell activation can also be assessed through measurement of secreted cytokines and chemokines. An activated immune cell (e.g., T cell, B cell, macrophage, monocyte, dendritic cell, eosinophil, basophil, mast cell, NK cell, ILC, or neutrophil) can produce pro-inflammatory cytokines and chemokines (e.g., IL-1β, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-18, TNFα, and IFN-γ). Activation can be assessed by measuring cytokine levels in a blood sample, lymph node biopsy, or tissue sample from a human subject or animal model, with higher levels of pro-inflammatory cytokines following treatment with a serotonin receptor inhibitor indicating increased activation, and lower levels indicating decreased activation. Activation can also be assessed in vitro by measuring cytokines secreted into the media by cultured cells. Cytokines can be measured using ELISA, western blot analysis, and other approaches for quantifying secreted proteins. Comparing results from before and after administration of a serotonin receptor inhibitor can be used to determine its effect. 
     The effect of a serotonin receptor inhibitor on T cell proliferation in a subject can be assessed by evaluation of markers of proliferation in T cells obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and T cells from the sample evaluated for Ki67 marker expression. T cell proliferation can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to T cells in vitro (e.g., T cells obtained from a subject, animal model, repository, or commercial source) and measuring Ki67 to evaluate T cell proliferation. Assessing whether a serotonin receptor inhibitor induces T cell proliferation can also be performed by in vivo (e.g., in a human subject or animal model) by collecting blood samples before and after serotonin receptor inhibitor administration and comparing T cell numbers, and in vitro by quantifying T cell numbers before and after contacting T cells with a serotonin receptor inhibitor. These approaches can also be used to measure the effect of a serotonin receptor inhibitor on proliferation of any immune cell (e.g., B cells, T cells, macrophages, monocytes, dendritic cells, NK cells, ILCs, mast cells, eosinophils, basophils, and neutrophils). Ki67 can be assessed using flow cytometry, immunohistochemistry, in situ hybridization, and other assays that allow for measurement of nuclear markers. Comparing results from before and after administration of a serotonin receptor inhibitor can be used to determine its effect. 
     The effect of a serotonin receptor inhibitor on cytotoxic T cell activation in a subject can be assessed by evaluation of T cell granule markers in T cells obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and T cells from the sample evaluated for granzyme or perforin expression. Cytotoxic T cell activation can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to cytotoxic T cells in vitro (e.g., cytotoxic T cells obtained from a subject, animal model, repository, or commercial source) and measuring the aforementioned markers to evaluate T cell proliferation. These markers can be detected in the media from cytotoxic T cell cultures. Techniques including ELISA, western blot analysis can be used to detect granzyme and perforin in conditioned media, flow cytometry, immunohistochemistry, in situ hybridization, and other assays can detect intracellular granzyme and perforin and their synthesis. Comparing results from before and after administration of a serotonin receptor inhibitor can be used to determine its effect. 
     The effect of a serotonin receptor inhibitor on circulating monocytes in a subject can be assessed by evaluation of cell surface markers on primary blood mononuclear cells obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and monocytes from the sample evaluated for CD14 and/or CD16 expression. Circulating monocytes can also be assessed using the same methods in an in vivo animal model. This assay can be performed by taking a blood sample before treatment with a serotonin receptor inhibitor and comparing it to a blood sample taken after treatment. CD14 and CD16 can be detected using flow cytometry, immunohistochemistry, western blot analysis, or any other technique that can measure cell surface protein levels. Comparing results from before and after administration of a serotonin receptor inhibitor can be used to determine its effect. This assay can be used to detect the number of monocytes in the bloodstream or to determine whether monocytes have adopted a CD14+/CD16+ phenotype, which indicates a pro-inflammatory function. 
     The effect of a serotonin receptor inhibitor on peripheral blood hematopoietic stem cells in a subject can be assessed by evaluation of cell surface markers on primary blood mononuclear cells obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and stem cells from the sample evaluated for one or more (2, 3 or 4 or more) specific markers: CD34, c-kit, Sca-1, or Thy1.1. Peripheral blood hematopoietic stem cells can also be assessed using the same methods in an in vivo animal model. This assay can be performed by taking a blood sample before treatment with a serotonin receptor inhibitor and comparing it to a blood sample taken after treatment. The aforementioned markers can be detected using flow cytometry, immunohistochemistry, western blot analysis, or any other technique that can measure cell surface protein levels. Comparing results from before and after administration of a serotonin receptor inhibitor can be used to determine its effect. This assay can be used to detect the number of stem cells mobilized into the bloodstream or to determine whether treatment induces differentiation into a particular hematopoietic lineage (e.g., decreased CD34 and increased GPA indicates differentiation into red blood cells, decreased CD34 and increased CD14 indicates differentiation into monocytes, decreased CD34 and increased CD11 b or CD68 indicates differentiation into macrophages, decreased CD34 and increased CD42b indicates differentiation into platelets, decreased CD34 and increased CD3 indicates differentiation into T cells, decreased CD34 and increased CD19 indicates differentiation into B cells, decreased CD34 and increased CD25 or CD69 indicates differentiation into activated T cells, decreased CD34 and increased CD1c, CD83, CD141, CD209, or MHC II indicates differentiation into dendritic cells, decreased CD34 and increased CD56 indicates differentiation into NK cells, decreased CD34 and increased CD15 indicates differentiation into neutrophils, decreased CD34 and increased 2D7 antigen, CD123, or CD203c indicates differentiation into basophils, and decreased CD34 and increased CD193, EMR1, or Siglec-8 indicates differentiation into eosinophils. 
     The effect of a serotonin receptor inhibitor on macrophage polarization in a subject can be assessed by evaluation of cellular markers in macrophages cells obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and macrophages from the sample evaluated for one of more (2, 3 or 4 or more) specific markers. Markers for M1 polarization include IL-12, TNF, IL-1β, IL-6, IL-23, MARCO, MHC-II, CD86, iNOS, CXCL9, and CXCL10. Markers for M2 polarized macrophages include IL-10, IL1-RA, TGFβ, MR, CD163, DC-SIGN, Dectin-1, HO-1, arginase (Arg-1), CCL17, CCL22 and CCL24. Macrophage polarization can also be assessed using the same methods in an in vivo animal model. This assay can also be performed on cultured macrophages obtained from a subject, an animal model, repository, or commercial source to determine how contacting a macrophage with a serotonin receptor inhibitor affects polarization. The aforementioned markers can be evaluated by comparing measurements obtained before and after administration of a serotonin receptor inhibitor to a subject, animal model, or cultured cell. Surface markers or intracellular proteins (e.g., MHC-11, CD86, iNOS, CD163, Dectin-1, HO-1, Arg-1, etc.) can be measured using flow cytometry, immunohistochemistry, in situ hybridization, or western blot analysis, and secreted proteins (e.g., IL-12, TNF, IL-1β, IL-10, TGFβ, 11_1-RA, chemokines CXC8, CXC9, CCL17, CCL22, and CCL24, etc.) can be measured using the same methods or by ELISA or western blot analysis of culture media or blood samples. Comparing results from before and after administration of a serotonin receptor inhibitor can be used to determine its effect. 
     The effect of a serotonin receptor inhibitor on macrophage phagocytosis in a subject can be assessed by culturing macrophages obtained from the subject with fluorescent beads. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and macrophages from the sample evaluated for engulfment of fluorescent beads. This assay can also be performed on cultured macrophages obtained from an animal model, repository, or commercial source to determine how contacting a macrophage with a serotonin receptor inhibitor affects phagocytosis. The same phagocytosis assay can be used to evaluate the effect of a serotonin receptor inhibitor on phagocytosis in other immune cells (e.g., neutrophils, monocytes, mast cells, B cells, eosinophils, or dendritic cells). Comparing results from before and after administration of a serotonin receptor inhibitor can be used to determine its effect on phagocytosis. 
     In some embodiments, phagocytosis is ADCP. ADCP can be assessed using similar methods to those described above by incubating immune cells (e.g., macrophages, neutrophils, monocytes, mast cells, B cells, eosinophils, or dendritic cells) isolated from a blood sample, lymph node biopsy, or tissue sample with fluorescent beads coated with IgG antibodies. In some embodiments, immune cells are incubated with a target cell line that has been pre-coated with antibodies to a surface antigen expressed by the target cell line. ADCP can be evaluated by measuring fluorescence inside the immune cell or quantifying the number of beads or cells engulfed. This assay can also be performed on cultured immune cells obtained from an animal model, repository, or commercial source to determine how contacting an immune cell with a serotonin receptor inhibitor affects ADCP. The ability of an immune cell to perform ADCP can also be evaluated by assessing expression of certain Fc receptors (e.g., FcγRIIa, FcγRIIIa, and FcγRI). Fc receptor expression can be assessed using flow cytometry, immunohistochemistry, in situ hybridization, or other assays that allow for measurement of cell surface markers. Comparing phagocytosis or Fc receptor expression before and after administration of a serotonin receptor inhibitor can be used to determine its effect on ACDP. In some embodiments, the serotonin receptor inhibitor increases ADCP of infectious agents. In some embodiments, the serotonin receptor inhibitor increases macrophage ADCP of antibody-coated tumor cells. 
     The effect of a serotonin receptor inhibitor on macrophage activation in a subject can be assessed by evaluation of cell surface markers on macrophages cells obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and macrophages from the sample evaluated for one or more (e.g., 1, 2, 3 or 4 or more) specific markers: F4/80, HLA molecules (e.g., MHC-II), CD80, CD68, CD11b, or CD86. Macrophage activation can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to macrophages in vitro (e.g., macrophages obtained from a subject, animal model, repository, or commercial source) and measuring the aforementioned markers to evaluate macrophage activation. These markers can be assessed using flow cytometry, immunohistochemistry, in situ hybridization, and other assays that allow for measurement of cell surface markers. As mentioned above, macrophage activation can also be evaluated based on cytokine production (e.g., pro-inflammatory cytokine production) as measured by ELISA and western blot analysis. Comparing results from before and after administration of a serotonin receptor inhibitor can be used to determine its effect. 
     The effect of a serotonin receptor inhibitor on antigen presentation in a subject can be assessed by evaluation of cell surface markers on antigen presenting cells (e.g., dendritic cells, macrophages, and B cells) obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and antigen presenting cells (e.g., dendritic cells, macrophages, and B cells) from the sample evaluated for one or more (e.g., 2, 3 or 4 or more) specific markers: CD11c, CD11b, HLA molecules (e.g., MHC-II), CD40, B7, IL-2, CD80 or CD86. Antigen presentation can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to antigen presenting cells (e.g., dendritic cells) in vitro (e.g., antigen presenting cells obtained from a subject, animal model, repository, or commercial source) and measuring the aforementioned markers to evaluate antigen presentation. These markers can be assessed using flow cytometry, immunohistochemistry, in situ hybridization, and other assays that allow for measurement of cell surface markers. Comparing results from before and after administration of a serotonin receptor inhibitor can be used to determine its effect. 
     The effect of a serotonin receptor inhibitor on antigen presenting cell migration in a subject can be assessed by evaluation of cell surface markers on antigen presenting cells (e.g., dendritic cells, B cells, and macrophages) obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and antigen presenting cells (e.g., dendritic cells, B cells, and macrophages) from the sample evaluated for CCR7 expression. Antigen presenting cell migration can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to antigen presenting cells (e.g., dendritic cells, B cells, and macrophages) in vitro (e.g., antigen presenting cells obtained from a subject, animal model, repository, or commercial source) and measuring CCR7 to evaluate antigen presenting cell migration. CCR7 can be assessed using flow cytometry, immunohistochemistry, in situ hybridization, and other assays that allow for measurement of cell surface markers. Comparing results from before and after administration of a serotonin receptor inhibitor can be used to determine its effect. 
     The effect of a serotonin receptor inhibitor on lymph node immune cell homing and cell egress in a subject can be assessed by evaluation of cell surface markers on T or B cells obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and T or B cells from the sample evaluated for one or more specific markers: CCR7 or S1PR1. Lymph node immune cell homing and cell egress can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to T or B cells in vitro (e.g., T or B cells obtained from a subject, animal model, repository, or commercial source) and measuring the aforementioned markers to evaluate T or B cell lymph node homing. These markers can also be used to assess lymph node homing and cell egress of dendritic cells and macrophages. CCR7 and S1PR1 can be assessed using flow cytometry, immunohistochemistry, in situ hybridization, and other assays that allow for measurement of cell surface markers. If using an animal model, lymph nodes or sites of inflammation can be imaged in vivo (e.g., using a mouse that expresses fluorescently labeled T or B cells) or after biopsy to determine whether T or B cell numbers change as a result of administration of a serotonin receptor inhibitor. Comparing results from before and after administration of a serotonin receptor inhibitor can be used to determine its effect. 
     In some embodiments, a serotonin receptor inhibitor increases homing or decreases egress of naïve T cells into or out of secondary lymphoid organs prior to antigen challenge (e.g., prior to administration of a vaccine) to generate a better antigen-specific response. 
     The effect of a serotonin receptor inhibitor on NK cell activation in a subject can be assessed by evaluation of cell surface markers on NK cells obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and NK cells from the sample evaluated for one or more (e.g., 2, 3 or 4 or more) specific markers: CD117, NKp46, CD94, CD56, CD16, KIR, CD69, HLA-DR, CD38, KLRG1, and TIA-1. NK cell activation can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to NK cells in vitro (e.g., NK cells obtained from a subject, animal model, repository, or commercial source) and measuring the aforementioned markers to evaluate NK cell activation. The effect of a serotonin receptor inhibitor can be determined by comparing results from before and after serotonin receptor inhibitor administration. 
     In some embodiments, activated NK cells have increased lytic function or are cytotoxic (e.g., capable of performing ADCC). The effect of a serotonin receptor inhibitor on ADCC can be assessed by incubating immune cells capable of ADCC (e.g., NK cells, monocytes, macrophages, neutrophils, eosinophils, dendritic cells, or T cells) with a target cell line that has been pre-coated with antibodies to a surface antigen expressed by the target cell line. ADCC can be assessed by measuring the number of surviving target cells with a fluorescent viability stain or by measuring the secretion of cytolytic granules (e.g., perforin, granzymes, or other cytolytic proteins released from immune cells). Immune cells can be collected from a blood sample, lymph node biopsy, or tissue sample from a human subject or animal model treated with a serotonin receptor inhibitor. This assay can also be performed by adding a serotonin receptor inhibitor to immune cells in vitro (e.g., immune cells obtained from a subject, animal model, repository, or commercial source). The effect of a serotonin receptor inhibitor on ADCC can be determined by comparing results from before and after serotonin receptor inhibitor administration. In some embodiments, the serotonin receptor inhibitor increases NK cell ADCC of antibody-opsonized infectious agents. In some embodiments, the serotonin receptor inhibitor increases NK cell ADCC of antibody-targeted tumors. 
     The effect of a serotonin receptor inhibitor on ILC activation in a subject can be assessed by evaluation of cell surface markers on ILCs obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and ILCs from the sample evaluated for one or more (e.g., 2, 3 or 4 or more) specific markers: NKp46, CD69, T-bet, RORα, GATA3, and RORγt. ILC activation can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to ILCs in vitro (e.g., ILCs obtained from a subject, animal model, repository, or commercial source) and measuring the aforementioned markers to evaluate ILC activation. The effect of a serotonin receptor inhibitor can be determined by comparing results from before and after serotonin receptor inhibitor administration. 
     In some embodiments, activated ILCs have increased lytic function or are cytotoxic (e.g., capable of performing ADCC). The effect of a serotonin receptor inhibitor on ADCC can be assessed by incubating immune cells capable of ADCC (e.g., ILCs, monocytes, macrophages, neutrophils, eosinophils, dendritic cells, or T cells) with a target cell line that has been pre-coated with antibodies to a surface antigen expressed by the target cell line. ADCC can be assessed by measuring the number of surviving target cells with a fluorescent viability stain or by measuring the secretion of cytolytic granules (e.g., perforin, granzymes, or other cytolytic proteins released from immune cells). Immune cells can be collected from a blood sample, lymph node biopsy, or tissue sample from a human subject or animal model treated with a serotonin receptor inhibitor. This assay can also be performed by adding a serotonin receptor inhibitor to immune cells in vitro (e.g., immune cells obtained from a subject, animal model, repository, or commercial source). The effect of a serotonin receptor inhibitor on ADCC can be determined by comparing results from before and after serotonin receptor inhibitor administration. In some embodiments, the serotonin receptor inhibitor decreases ILC ADCC of auto-antibody coated cells (e.g., to treat autoimmune disease). In some embodiments, the serotonin receptor inhibitor increases ILC ADCC of antibody-opsonized infectious agents. 
     The effect of a serotonin receptor inhibitor on mast cell degranulation in a subject can be assessed by evaluation of markers in mast cells obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and mast cells from the sample evaluated for one or more (e.g., 1, 2, 3 or 4 or more) specific markers: IgE, histamine, IL-4, TNFα, CD300a, tryptase, or MMP9. Mast cell degranulation can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to mast cells in vitro (e.g., mast cells obtained from a subject, animal model, repository, or commercial source) and measuring the aforementioned markers to evaluate mast cell degranulation. Some of these markers (e.g., histamine, TNFα, and IL-4) can be detected by measuring levels in the mast cell culture medium after mast cells are contacted with a serotonin receptor inhibitor. The effect of a serotonin receptor inhibitor can be determined by comparing results from before and after serotonin receptor inhibitor administration. This approach can also be used to evaluate the effect of a serotonin receptor inhibitor on degranulation by other cells, such as neutrophils (markers: CD11b, CD13, CD18, CD45, CD15, CD66b IL-1β, IL-8, and IL-6), eosinophils (markers: major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPX), eosinophil-derived neurotoxin (EDN)), basophils (markers: histamine, heparin, chondroitin, elastase, lysophospholipase, and LTD-4), NK cells (markers: LAMP-1, perforin, and granzymes), and cytotoxic T cells (markers: LAMP-1, perforin, and granzymes). Markers can be detected using flow cytometry, immunohistochemistry, ELISA, western blot analysis, or in situ hybridization. 
     The effect of a serotonin receptor inhibitor on neutrophil recruitment in a subject can be assessed by evaluation of cell surface markers on neutrophils obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and neutrophils from the sample evaluated for one or more (e.g., 1, 2, 3 or 4 or more) specific markers: CD11b, CD14, CD114, CD177, CD354, or CD66. To determine whether neutrophils are being recruited to a specific site (e.g., a tumor), the same markers can be measured in a tumor biopsy. Neutrophil recruitment can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to neutrophils in vitro (e.g., neutrophils obtained from a subject, animal model, repository, or commercial source) and measuring the aforementioned markers to evaluate neutrophil recruitment. These markers can be assessed using flow cytometry, immunohistochemistry, in situ hybridization, and other assays that allow for measurement of cell surface markers. The effect of a serotonin receptor inhibitor can be determined by comparing results from before and after serotonin receptor inhibitor administration. 
     The effect of a serotonin receptor inhibitor on eosinophil recruitment in a subject can be assessed by evaluation of cell surface markers on eosinophil obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and eosinophils from the sample evaluated for one or more (e.g., 1, 2, 3 or 4 or more) specific markers: CD15, IL-3R, CD38, CD106, CD294 or CD85G. To determine whether eosinophils are being recruited to a specific site (e.g., a tumor), the same markers can be measured in a tumor biopsy. Eosinophil recruitment can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to eosinophils in vitro (e.g., eosinophils obtained from a subject, animal model, repository, or commercial source) and measuring the aforementioned markers to evaluate eosinophil recruitment. These markers can be assessed using flow cytometry, immunohistochemistry, in situ hybridization, and other assays that allow for measurement of cell surface markers. The effect of a serotonin receptor inhibitor can be determined by comparing results from before and after serotonin receptor inhibitor administration. 
     The effect of a serotonin receptor inhibitor on NKT cell activation in a subject can be assessed by evaluation of cell surface markers on NKT cells obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and NKT cells from the sample evaluated for one or more specific markers: CD272 or CD352. Activated NKT cells produce IFN-γ, IL-4, GM-CSF, IL-2, IL-13, IL-17, IL-21 and TNFα. NKT cell activation can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to NKT cells in vitro (e.g., NKT cells obtained from a subject, animal model, repository, or commercial source) and measuring the aforementioned markers to evaluate NKT cell activation. Cell surface markers CD272 and CD352 can be assessed using flow cytometry, immunohistochemistry, in situ hybridization, and other assays that allow for measurement of cell surface markers. The secreted proteins can be detected in blood samples or cell culture media using ELISA, western blot analysis, or other methods for detecting proteins in solution. The effect of a serotonin receptor inhibitor can be determined by comparing results from before and after serotonin receptor inhibitor administration. 
     The effects of a serotonin receptor inhibitor on B cell activation in a subject can be assessed by evaluation of cell surface markers on B cells obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and B cells from the sample evaluated for one or more (e.g., 2, 3 or 4 or more) specific markers: CD19, CD20, CD40, CD80, CD86, CD69, IgM, IgD, IgG, IgE, or IgA. B cell activation can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to B cells in vitro (e.g., B cells obtained from a subject, animal model, repository, or commercial source) and measuring the aforementioned markers to evaluate B cell activation. These markers can be assessed using flow cytometry, immunohistochemistry, in situ hybridization, and other assays that allow for measurement of cell surface markers. The effect of a serotonin receptor inhibitor can be determined by comparing results from before and after serotonin receptor inhibitor administration. 
     The effect of a serotonin receptor inhibitor on regulatory T cell differentiation in a subject can be assessed by evaluation of markers in regulatory T cells obtained from the subject. A blood sample, lymph node biopsy, or tissue sample can be collected from a subject and regulatory T cells from the sample evaluated for one or more (e.g., 1, 2, 3, 4 or more) specific markers: CD4, CD25, or FoxP3. Regulatory T cell differentiation can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to regulatory T cells in vitro (e.g., regulatory T cells obtained from a subject, animal model, repository, or commercial source) and measuring the aforementioned markers to evaluate regulatory T cell differentiation. These markers can be assessed using flow cytometry, immunohistochemistry, in situ hybridization, and other assays that allow for measurement of cellular markers. The effect of a serotonin receptor inhibitor can be determined by comparing results from before and after serotonin receptor inhibitor administration. 
     The effect of a serotonin receptor inhibitor on innervation of a lymph node or secondary lymphoid organ can be assessed by evaluation of neuronal markers in a lymph node or secondary lymphoid organ biopsy sample obtained from a human subject or animal model. A biopsy can be collected from the subject and evaluated for one or more (e.g., 1, 2, 3, 4, or 4 or more) neuronal markers selected from: Neurofilament, synapsin, synaptotagmin, or neuron specific enolase. Lymph node innervation can also be assessed using electrophysiological approaches (e.g., recording neuronal activity in a lymph node or secondary lymphoid organ in a human subject or animal model). The effect of a serotonin receptor inhibitor can be determined by comparing results from before and after serotonin receptor inhibitor administration. 
     The serotonin receptor inhibitor can also reduce the number of nerve fibers in the affected tissue or reduce the activity of peripheral nerve fibers in the affected tissue. For example, the method includes administering to the subject (e.g., a human subject or animal model) a serotonin receptor inhibitor in an amount and for a time sufficient to reduce the number of nerve fibers in the affected tissue or reduce the activity of peripheral nerve fibers in the affected tissue. The affected tissue can be a lymph node, a lymphoid organ, a tumor, a tumor micro-environment, a site of metastasis or the bone marrow niche. The number of nerve fibers in the affected tissue or the activity of peripheral nerve fibers in the affected tissue can be decreased in the subject at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, compared to before the administration. The number of nerve fibers in the affected tissue or the activity of peripheral nerve fibers in the affected tissue can be decreased in the subject between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%. 
     The serotonin receptor inhibitor can also increase the number of nerve fibers in the affected tissue or increase the activity of peripheral nerve fibers in the affected tissue. For example, the method includes administering to the subject (e.g., a human subject or animal model) a serotonin receptor inhibitor in an amount and for a time sufficient to increase the number of nerve fibers in the affected tissue or increase the activity of peripheral nerve fibers in the affected tissue. The affected tissue can be a lymph node, a lymphoid organ, a tumor, a tumor micro-environment, a site of metastasis, or the bone marrow niche. The number of nerve fibers in the affected tissue or the activity of peripheral nerve fibers in the affected tissue can be increased in the subject at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80% or more, compared to before the administration. The number of nerve fibers in the affected tissue or the activity of peripheral nerve fibers in the affected tissue can be increased in the subject between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%. 
     The nerve fibers that are modulated can be part of the peripheral nervous system, e.g., a somatic nerve, an autonomic nerve, a sensory nerve, a cranial nerve, an optic nerve, an olfactory nerve, a sympathetic nerve, a parasympathetic nerve, a chemoreceptor, a photoreceptor, a mechanoreceptor, a thermoreceptor, a nociceptor, an efferent nerve fiber, or an afferent nerve fiber. 
     The effect of a serotonin receptor inhibitor on immune cell cytokine production can be assessed by evaluation of cellular markers in an immune cell sample obtained from a human subject or animal model. A blood sample, lymph node biopsy, or tissue sample can be collected for the subject and evaluated for one or more (e.g., 1, 2, 3, 4, or 4 or more) cytokine markers selected from: pro-inflammatory cytokines (e.g., IL-1β, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-18, TNFα, IFNγ, GMCSF), pro-survival cytokines (e.g., IL-2, IL-4, IL-6, IL-7, and IL-15) and anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13, IFNα, and TGFβ). Some cytokines can function as both pro- and anti-inflammatory cytokines depending on context or indication (e.g., IL-4 is often categorized as an anti-inflammatory cytokine, but plays a pro-inflammatory role in mounting an allergic or anti-parasitic immune response). Cytokines can be also detected in the culture media of immune cells contacted with a serotonin receptor inhibitor. Cytokines can be detected using ELISA, western blot analysis, or other methods for detecting protein levels in solution. The effect of a serotonin receptor inhibitor can be determined by comparing results from before and after serotonin receptor inhibitor administration. 
     In some embodiments, a serotonin receptor inhibitor decreases or prevents the development of ectopic or TLOs to decrease local inflammation in autoimmune diseases. TLOs are highly similar to SLOs and exhibit T and B cell compartmentalization, APCs such as DCs and follicular DCs, stromal cells, and a highly organized vascular system of high endothelial venules. In some embodiments, a serotonin receptor inhibitor decreases or prevents the development of HEVs within tertiary lymphoid organs to decrease local inflammation in autoimmune diseases. HEVs can be detected using the monoclonal antibody MECA-79. 
     In some embodiments, a serotonin receptor inhibitor modulates dendritic cell maturation (e.g., activation). Dendritic cell maturation can be increased to promote their migration from peripheral tissues into secondary lymphoid organs to improve T cell activation in the draining lymph node (e.g., to increase vaccine efficacy or to increase priming of an anti-tumor immune response). Dendritic cell maturation can be decreased to decrease their migration from peripheral tissues into secondary lymphoid organs to inhibit T cell activation in the draining lymph node (e.g., to improve outcomes in organ transplantation or to reduce the severity of or treat autoimmune diseases). 
     The effect of a serotonin receptor inhibitor on immune cell recruitment or migration to a tumor can be assessed by evaluation of cellular markers on immune cells obtained from a human subject or animal model. A blood sample or tumor biopsy can be collected from a human subject or animal model and T cells, B cells, dendritic cells, or macrophages can be evaluated for marker CCR7. Immune cell recruitment to a tumor can also be assessed by taking a tumor biopsy before and after administration of a serotonin receptor inhibitor to a human subject or animal model and quantifying the number of immune cells in the tumor. Immune cells can be identified based on the markers described above and others listed in Table 4. A bulk gene expression signature can also be deconvolved into signatures indicative of specific immune cell types using published algorithms, such as the CIBERSORT algorithm described in Gentles et al, Nature Medicine 21:938 2015. Mouse models of cancer that express fluorescent reporters in immune cells can also be used for live imaging-based approaches to evaluate the effect of a serotonin receptor inhibitor on immune cell migration or recruitment to a tumor. Immune cell recruitment or migration to a tumor can also be assessed by adding a serotonin receptor inhibitor to immune cells in vitro (e.g., immune cells obtained from a subject, animal model, repository, or commercial source) and measuring CCR7 to evaluate immune cell migration or recruitment. The effect of a serotonin receptor inhibitor can be determined by comparing results from before and after serotonin receptor inhibitor administration. 
     In some embodiments, a serotonin receptor inhibitor increases homing or decreases egress of naïve T cells into or out of secondary lymphoid organs prior to inducing immunogenic tumor cell death to generate a better anti-tumor response (e.g., prior to radio- or chemotherapy). In some embodiments, a serotonin receptor inhibitor increases homing or decreases egress of immune cells into or out of the tumor microenvironment to turn a “cold tumor” into a “hot tumor” prior to immunotherapy. In some embodiments, a serotonin receptor inhibitor increases homing or decreases egress of effector immune cell subsets into or out of the tumor microenvironment to promote anti-tumor immunity. In some embodiments, a serotonin receptor inhibitor decreases homing or increases egress of immunosuppressive immune subsets into or out of the tumor microenvironment to promote anti-tumor immunity. In some embodiments, a serotonin receptor inhibitor induces or increases the development of HEVs within the tumor microenvironment to increase TIL recruitment. HEVs can be detected using the monoclonal antibody MECA-79. In some embodiments, the serotonin receptor inhibitor induces or increases the development of TLOs within the tumor microenvironment to increase TIL recruitment. TLOs can be recognized by their similarity to SLOs, as they exhibit T and B cell compartmentalization, APCs such as DCs and follicular DCs, stromal cells, and a highly organized vascular system of HEVs. 
     The effect of a serotonin receptor inhibitor on NK cell lytic function can be assessed by evaluation of cellular markers on NK cells obtained from a human subject or animal model. A blood sample or tumor biopsy can be collected from a human subject or animal model and NK cells can be evaluated for one or more (e.g., 1, 2, 3 or more) of the markers: CD95L, CSD154, and CD253. NK cell lytic function can also be assessed using the same methods in an in vivo animal model. This assay can also be performed by adding a serotonin receptor inhibitor to NK cells in vitro (e.g., NK cells obtained from a subject, animal model, repository, or commercial source) and measuring the aforementioned markers to evaluate NK cell activation. These markers can be assessed using flow cytometry, immunohistochemistry, in situ hybridization, and other assays that allow for measurement of cell surface markers. The effect of a serotonin receptor inhibitor can be determined by comparing results from before and after serotonin receptor inhibitor administration. 
     Table 4 lists additional markers and relevant assays that may be used to assess the level, function and/or activity of immune cells in the methods described herein. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 ASSESSMENT OF IMMUNE CELL PHENOTYPES 
               
            
           
           
               
               
               
               
            
               
                 IMMUNE  
                 ASSOCIATED 
                   
                   
               
               
                 CELL 
                 CYTOKINES 
                 MARKER 
                 ASSAYS 
               
               
                   
               
               
                 Th1 helper 
                 IFN-γ 
                 CD4 
                 ELISPOT 
               
               
                   
                 IL-2 
                 CD94 
                 In situ  
               
               
                   
                 IL-12 
                 CD119 
                 hybridization 
               
               
                   
                 IL-18 
                 (IFNγ R1) 
                 Immunohisto- 
               
               
                   
                 IL-27 
                 CD183 
                 chemistry 
               
               
                   
                 TNFα 
                 (CXCR3) 
                 Limiting dilution  
               
               
                   
                 TNFβ/LTα 
                 CD186 
                 Analysis 
               
               
                   
                   
                 (CXCR6) 
                 Single-cell PCR 
               
               
                   
                   
                 CD191 
                 In vivo capture  
               
               
                   
                   
                 (CCR1) 
                 assay 
               
               
                   
                   
                 CD195 
                 ELISA 
               
               
                   
                   
                 (CCR5) 
                 Flow cytometry 
               
               
                   
                   
                 CD212 (IL- 
                   
               
               
                   
                   
                 12Rβ1&amp;2) 
                   
               
               
                   
                   
                 CD254 
                   
               
               
                   
                   
                 (RANKL) 
                   
               
               
                   
                   
                 CD278 
                   
               
               
                   
                   
                 (ICOS) 
                   
               
               
                   
                   
                 IL-18R 
                   
               
               
                   
                   
                 MRP1 
                   
               
               
                   
                   
                 NOTCH3 
                   
               
               
                   
                   
                 TCR 
                   
               
               
                   
                   
                 TIM3 
                   
               
               
                 Th2 helper 
                 IL-4 
                 CD4 
                 ELISPOT 
               
               
                   
                 IL-2 
                 CD30 
                 In situ  
               
               
                   
                 IL-6 
                 CD119 
                 hybridization 
               
               
                   
                 IL-33 
                 (IFNγ R1) 
                 Immunohisto- 
               
               
                   
                 IL-17E (IL-25) 
                 CD184 
                 chemistry 
               
               
                   
                 IL-31 
                 (CXCR4) 
                 Limiting dilution 
               
               
                   
                 IL-3 
                 CD185 
                 Analysis 
               
               
                   
                 IL-10 
                 (CXCR5) 
                 Single-cell PCR 
               
               
                   
                 IL-13 
                 CD193 
                 In vivo capture 
               
               
                   
                   
                 (CCR3) 
                 assay 
               
               
                   
                   
                 CD194 
                 ELISA 
               
               
                   
                   
                 (CCR4) 
                 Flow cytometry 
               
               
                   
                   
                 CD197 
                   
               
               
                   
                   
                 (CCR7) 
                   
               
               
                   
                   
                 CD278 
                   
               
               
                   
                   
                 (ICOS) 
                   
               
               
                   
                   
                 CD294 
                   
               
               
                   
                   
                 (CRTh2) 
                   
               
               
                   
                   
                 CDw198 
                   
               
               
                   
                   
                 (CCR8) 
                   
               
               
                   
                   
                 IL-17RB 
                   
               
               
                   
                   
                 IL-33Rα 
                   
               
               
                   
                   
                 (ST2) 
                   
               
               
                   
                   
                 NOTCH1 
                   
               
               
                   
                   
                 NOTCH2 
                   
               
               
                   
                   
                 TCR 
                   
               
               
                   
                   
                 TIM1 
                   
               
               
                 Th17 helper 
                 TGFβ1 
                 CD4 
                 ELISPOT 
               
               
                   
                 IL-1β 
                 CD27 
                 In situ  
               
               
                   
                 IL-6 
                 CD62L 
                 hybridization 
               
               
                   
                 IL-21 
                 CD127 (IL- 
                 Immunohisto- 
               
               
                   
                 IL-23 
                 7R) 
                 chemistry 
               
               
                   
                 IL-17A 
                 CD161 
                 Limiting dilution 
               
               
                   
                 IL-17F 
                 CD184 
                 Analysis 
               
               
                   
                 IL-22 
                 (CXCR4) 
                 Single-cell PCR 
               
               
                   
                 IL-26 
                 CD194 
                 In vivo capture 
               
               
                   
                 GM-CSF 
                 (CCR4) 
                 assay 
               
               
                   
                 MIP-3α 
                 CD196 
                 ELISA 
               
               
                   
                 TNFα 
                 (CCR6) 
                 Flow cytometry 
               
               
                   
                   
                 CD197 
                   
               
               
                   
                   
                 (CCR7) 
                   
               
               
                   
                   
                 CD212b1 
                   
               
               
                   
                   
                 (IL-12Rβ1) 
                   
               
               
                   
                   
                 CD213a1 
                   
               
               
                   
                   
                 (IL-13Rα1) 
                   
               
               
                   
                   
                 CD278 
                   
               
               
                   
                   
                 (ICOS) 
                   
               
               
                   
                   
                 IL-1R1 
                   
               
               
                   
                   
                 IL-21R 
                   
               
               
                   
                   
                 IL-23R 
                   
               
               
                 Treg 
                 TGFβ1 
                 CD4 
                 ELISPOT 
               
               
                   
                 IL-2 
                 CD25 
                 In situ  
               
               
                   
                 IL-10 
                 CD39 
                 hybridization 
               
               
                   
                 IL-35 
                 CD73 
                 Immunohisto- 
               
               
                   
                   
                 CD45RO 
                 chemistry 
               
               
                   
                   
                 CD121a (IL- 
                 Limiting dilution 
               
               
                   
                   
                 1R1) 
                 Analysis 
               
               
                   
                   
                 CD121b (IL- 
                 Single-cell PCR 
               
               
                   
                   
                 1R2) 
                 In vivo capture 
               
               
                   
                   
                 CD127low 
                 assay 
               
               
                   
                   
                 CD134 
                 ELISA 
               
               
                   
                   
                 (OX40) 
                 Flow cytometry 
               
               
                   
                   
                 CD137 (4- 
                   
               
               
                   
                   
                 1BB) 
                   
               
               
                   
                   
                 CD152 
                   
               
               
                   
                   
                 (CTLA-4) 
                   
               
               
                   
                   
                 CD357 
                   
               
               
                   
                   
                 (GITR/AITR) 
                   
               
               
                   
                   
                 Foxp3 
                   
               
               
                   
                   
                 FR4 (m) 
                   
               
               
                   
                   
                 GARP 
                   
               
               
                   
                   
                 (activated) 
                   
               
               
                   
                   
                 Helios 
                   
               
               
                   
                   
                 LAP/TGFβ 
                   
               
               
                   
                   
                 (activated) 
                   
               
               
                   
                   
                 TIGIT 
                   
               
               
                 Dendritic  
                 GM-CSF 
                 CD1a 
                 ELISPOT 
               
               
                 cell 
                 IFNγ 
                 CD8 
                 In situ  
               
               
                   
                 IL-4 
                 CD11c 
                 hybridization 
               
               
                   
                 GM-CSF 
                 CD80 
                 Immunohisto- 
               
               
                   
                 IFNα 
                 CD83 
                 chemistry 
               
               
                   
                 IL-1α 
                 CD85 (ILT)  
                 Limiting dilution 
               
               
                   
                 IL-1β 
                 family 
                 Analysis 
               
               
                   
                 IL-6 
                 CD86 
                 Single-cell PCR 
               
               
                   
                 IL-8 
                 CD141 (h) 
                 In vivo capture 
               
               
                   
                 IL-10 
                 CD169 
                 assay 
               
               
                   
                 IL-12 
                 CD172 
                 ELISA 
               
               
                   
                 IL-15 
                 CD184  
                 Flow cytometry 
               
               
                   
                 IL-18 
                 (CXCR4) 
                   
               
               
                   
                 IL-23 
                 CD197 (CCR7) 
                   
               
               
                   
                 IL-27 
                 CD205 
                   
               
               
                   
                 IP-10 
                 CD206 
                   
               
               
                   
                 M-CSF 
                 CD207 
                   
               
               
                   
                 RANTES (CCL5) 
                 CD209 
                   
               
               
                   
                 TGFβ 
                 CD215 (IL-15R) 
                   
               
               
                   
                 TNFα 
                 CD282 (TLR2) 
                   
               
               
                   
                   
                 CD284 (TLR4) 
                   
               
               
                   
                   
                 CD286 (TLR6) 
                   
               
               
                   
                   
                 Clec Family 
                   
               
               
                 Macrophages/ 
                 FLT3 Ligand 
                 CD11b 
                 ELISPOT 
               
               
                 Monocytes 
                 GM-CSF 
                 CD14 (mono) 
                 In situ  
               
               
                   
                 M-CSF 
                 CD16 
                 hybridization 
               
               
                   
                 CXCL9 
                 CD32 
                 Immunohisto- 
               
               
                   
                 CXCL10 
                 CD68 
                 chemistry 
               
               
                   
                 CXCL11 
                 CD85a (ILT5) 
                 Limiting dilution 
               
               
                   
                 G-CSF 
                 CD163 
                 Analysis 
               
               
                   
                 GM-CSF 
                 CD169 
                 Single-cell PCR 
               
               
                   
                 IFNβ 
                 CD195 (CCR5) 
                 In vivo capture 
               
               
                   
                 IL-1α 
                 CD204 
                 assay 
               
               
                   
                 IL-1β 
                 CD206 
                 ELISA 
               
               
                   
                 IL-6 
                 CD282 (TLR2) 
                 Flow cytometry 
               
               
                   
                 IL-8 
                 CD284 (TLR4) 
                   
               
               
                   
                 IL-10 
                 CD286 (TLR6) 
                   
               
               
                   
                 IL-12p40 &amp; p70 
                 CD354 (Trem-1) 
                   
               
               
                   
                 IL-18 
                 Clec Family 
                   
               
               
                   
                 IL-23 
                 F4/80 (m) 
                   
               
               
                   
                 IL-27 
                 HLA-DR 
                   
               
               
                   
                 M-CSF 
                   
                   
               
               
                   
                 MIP-2α (CXCL2) 
                   
                   
               
               
                   
                 RANTES (CCL5) 
                   
                   
               
               
                   
                 TNFα 
                   
                   
               
               
                 Natural  
                 IL-2 
                 CD16 
                 ELISPOT 
               
               
                 Killer Cell 
                 IL-12 
                 CD25 
                 In situ  
               
               
                   
                 IL-15/IL-15R 
                 CD49b 
                 hybridization 
               
               
                   
                 IL-18 
                 CD56 (h) 
                 Immunohisto- 
               
               
                   
                 Granzyme B 
                 CD94 
                 chemistry 
               
               
                   
                 IL-17A 
                 CD158 family  
                 Limiting dilution 
               
               
                   
                 IL-22 
                 (KIR) (h) 
                 Analysis 
               
               
                   
                 MIP-1α (CCL3) 
                 CD181 (CXCR1) 
                 Single-cell PCR 
               
               
                   
                 MIP-1β (CCL4) 
                 CD183 (CXCR3) 
                 In vivo capture 
               
               
                   
                 Perforin 
                 CD184 (CXCR4) 
                 assay 
               
               
                   
                 RANTES (CCL5) 
                 CD186 (CXCR6) 
                 ELISA 
               
               
                   
                 TNFα 
                 CD192  
                 Flow cytometry 
               
               
                   
                   
                 (activated) 
                   
               
               
                   
                   
                 CD195 (CCR5) 
                   
               
               
                   
                   
                 CD197 (CCR7) 
                   
               
               
                   
                   
                 CD212 (IL-12R) 
                   
               
               
                   
                   
                 CD244 
                   
               
               
                   
                   
                 CD314  
                   
               
               
                   
                   
                 (NKG2D) 
                   
               
               
                   
                   
                 CX3CR1 
                   
               
               
                   
                   
                 Eomes 
                   
               
               
                   
                   
                 KLRG1 
                   
               
               
                   
                   
                 Ly49 family (m) 
                   
               
               
                   
                   
                 NK1.1 
                   
               
               
                   
                   
                 NKG2A 
                   
               
               
                   
                   
                 NKp30, NKp42 
                   
               
               
                   
                   
                 NKp44 (h) 
                   
               
               
                   
                   
                 NKp46 
                   
               
               
                   
                   
                 T-bet 
                   
               
               
                 Innate  
                 IFN-γ 
                 CD335 (NKp46) 
                 ELISPOT 
               
               
                 Lymphoid 
                 TNF 
                 CD336 (NKp44) 
                 In situ  
               
               
                 Cell 1 (ILC1) 
                   
                 CD94 
                 hybridization 
               
               
                   
                   
                 CD56 (NCAM) 
                 Immunohisto- 
               
               
                   
                   
                 CD103 
                 chemistry 
               
               
                   
                   
                 T-bet 
                 Limiting dilution 
               
               
                   
                   
                   
                 Analysis 
               
               
                   
                   
                   
                 Single-cell PCR 
               
               
                   
                   
                   
                 In vivo capture 
               
               
                   
                   
                   
                 assay 
               
               
                   
                   
                   
                 ELISA 
               
               
                   
                   
                   
                 Flow cytometry 
               
               
                 Innate  
                 Areg 
                 CD127 
                 ELISPOT 
               
               
                 Lymphoid 
                 IL-5 
                 CRTH2 
                 In situ  
               
               
                 Cell 2 (ILC2) 
                 IL-13 
                 ST2 (IL-33R) 
                 hybridization 
               
               
                   
                   
                 RORα 
                 Immunohisto- 
               
               
                   
                   
                 GATA3 
                 chemistry 
               
               
                   
                   
                   
                 Limiting dilution 
               
               
                   
                   
                   
                 Analysis 
               
               
                   
                   
                   
                 Single-cell PCR 
               
               
                   
                   
                   
                 In vivo capture 
               
               
                   
                   
                   
                 assay 
               
               
                   
                   
                   
                 ELISA 
               
               
                   
                   
                   
                 Flow cytometry 
               
               
                 Innate  
                 CCL3 
                 CD127 
                 ELISPOT 
               
               
                 Lymphoid 
                 LTs 
                 CD117 (c-kit) 
                 In situ 
               
               
                 Cell 3 (ILC3) 
                 IL-22 
                 CD335 (NKp46) 
                 hybridization 
               
               
                   
                 IL-17 
                 CD336 (NKp44) 
                 Immunohisto- 
               
               
                   
                 IFN-γ 
                 IL-23R 
                 chemistry 
               
               
                   
                   
                 RORγt 
                 Limiting dilution 
               
               
                   
                   
                   
                 Analysis 
               
               
                   
                   
                   
                 Single-cell PCR 
               
               
                   
                   
                   
                 In vivo capture 
               
               
                   
                   
                   
                 assay 
               
               
                   
                   
                   
                 ELISA 
               
               
                   
                   
                   
                 Flow cytometry 
               
               
                 Activated B 
                 Antibodies 
                 CD19 
                 Flow cytometry 
               
               
                 cell/ 
                 IgM 
                 CD25 
                   
               
               
                 Plasma cells 
                 IgG 
                 CD30 
                   
               
               
                   
                 IgD 
                 IgM 
                   
               
               
                   
                 IgE 
                 CD19 
                   
               
               
                   
                 IgA 
                 IgG 
                   
               
               
                   
                   
                 CD27 
                   
               
               
                   
                   
                 CD38 
                   
               
               
                   
                   
                 CD78 
                   
               
               
                   
                   
                 CD138 
                   
               
               
                   
                   
                 CD319 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 EXAMPLES OF HUMAN CHEMOKINES 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 Alternate 
                   
                   
                   
               
               
                 Systematic 
                 Human 
                 human 
                   
                 Human receptor(s) and 
                 Known 
               
               
                 name 
                 gene 
                 names 
                 Expression 
                 their expression 
                 functions 
               
               
                   
               
               
                 C Family 
                   
                   
                   
                   
                   
               
               
                 XCL1 
                 XCL1 
                 Lymphotactin, 
                 activated CD8 +  T 
                 XCR1: cross-presenting 
                 migration and 
               
               
                   
                   
                 SCM-1 alpha, 
                 cells and other 
                 drendritic cells 
                 activation of 
               
               
                   
                   
                 ATAC 
                 MHCI restricted T 
                   
                 lymphocytes, 
               
               
                   
                   
                   
                 cells 
                   
                 NK cells 
               
               
                 XCL2 
                 XCL2 
                 SCM-1 beta 
                 expressed in 
                 XCR1: cross-presenting 
                 migration and 
               
               
                   
                   
                   
                 activated T cells 
                 drendritic cells 
                 activation of 
               
               
                   
                   
                   
                   
                   
                 lymphocytes, 
               
               
                   
                   
                   
                   
                   
                 NK cells 
               
               
                 CX3C Family 
                   
                   
                   
                   
                   
               
               
                 CX3CL1 
                 CX3CL1 
                 Fractalkine, 
                 brain, heart, lung,  
                 CX3CR1: lymphocytes, 
                 migration and 
               
               
                   
                   
                 Neurotactin, 
                 kidney, skeletal 
                 monocytes 
                 adhesion of 
               
               
                   
                   
                 ABCD-3 
                 muscle and testis. 
                   
                 lymphocytes 
               
               
                   
                   
                   
                 Up-regulated in 
                   
                 and monocytes 
               
               
                   
                   
                   
                 endothelial cells and 
                   
                   
               
               
                   
                   
                   
                 microglia by 
                   
                   
               
               
                   
                   
                   
                 inflammation 
                   
                   
               
               
                 CC Family 
                   
                   
                   
                   
                   
               
               
                 CCL1 
                 CCL1 
                 I-309 
                 activated T cells 
                 CCR8: natural killer 
                 migration of 
               
               
                   
                   
                   
                   
                 cells, monocytes and 
                 monocytes, NK 
               
               
                   
                   
                   
                   
                 lymphocytes 
                 cells, immature 
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                 B cells and 
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                 DCs 
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CCL2 
                 CCL2 
                 MCP-1, 
                 monocytes, 
                 CCR2: monocytes 
                 migration of 
               
               
                   
                   
                 MCAF,  
                 macrophages and 
                 CCR4: lymphocytes 
                 monocytes and 
               
               
                   
                   
                 HC11 
                 dendritic cells, 
                 CCR11: unkown 
                 basophils 
               
               
                   
                   
                   
                 activated NK cells 
                 D6: lymphocytes, 
                   
               
               
                   
                   
                   
                   
                 lymphatic endothelial 
                   
               
               
                   
                   
                   
                   
                 cells, macrophages 
                   
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                   
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CCL3 
                 CCL3 
                 MIP-1 alpha, 
                 T cells, B cells, and 
                 CCR1: lymphocytes, 
                 adhesion of 
               
               
                   
                   
                 LD78 alpha, 
                 monocytes after 
                 monocytes, airway  
                 lymphocytes 
               
               
                   
                   
                 GOS19, 
                 antigen or mitogen 
                 smooth muscle cells 
                   
               
               
                   
                   
                 Pat464 
                 stimulation 
                 CCR4: lymphocytes 
                   
               
               
                   
                   
                   
                   
                 CCR5: T cells, 
                   
               
               
                   
                   
                   
                   
                 macrophages, dendritic 
                   
               
               
                   
                   
                   
                   
                 cells, eosinophils and 
                   
               
               
                   
                   
                   
                   
                 microglia 
                   
               
               
                   
                   
                   
                   
                 D6: lymphocytes, 
                   
               
               
                   
                   
                   
                   
                 lymphatic endothelial 
                   
               
               
                   
                   
                   
                   
                 cells, macrophages 
                   
               
               
                 CCL3L1 
                 CCL3L1 
                 LD78 beta 
                 Unknown 
                 CCR1: lymphocytes, 
                 migration of 
               
               
                   
                   
                   
                   
                 monocytes, airway 
                 lymphocytes 
               
               
                   
                   
                   
                   
                 smooth muscle cells 
                 and monocytes 
               
               
                   
                   
                   
                   
                 CCR3: eosinophils, 
                   
               
               
                   
                   
                   
                   
                 basophils, Th2 cells, 
                   
               
               
                   
                   
                   
                   
                 CD34 +  hematopoetic 
                   
               
               
                   
                   
                   
                   
                 progenitors, 
                   
               
               
                   
                   
                   
                   
                 keratinocytes, mast cells 
                   
               
               
                   
                   
                   
                   
                 CCR5: T cells, 
                   
               
               
                   
                   
                   
                   
                 macrophages, dendritic 
                   
               
               
                   
                   
                   
                   
                 cells, eosinophils and 
                   
               
               
                   
                   
                   
                   
                 microglia 
                   
               
               
                   
                   
                   
                   
                 D6: lymphocytes, 
                   
               
               
                   
                   
                   
                   
                 lymphatic endothelial 
                   
               
               
                   
                   
                   
                   
                 cells, macrophages 
                   
               
               
                 CCL3L3 
                 CCL3L3 
                 LD78 beta 
                 Unknown 
                 CCR1: lymphocytes,  
                 migration of 
               
               
                   
                   
                   
                   
                 monocytes, airway 
                 lymphocytes 
               
               
                   
                   
                   
                   
                 smooth muscle cells 
                 and monocytes 
               
               
                   
                   
                   
                   
                 CCR3: eosinophils, 
                   
               
               
                   
                   
                   
                   
                 basophils, Th2 cells, 
                   
               
               
                   
                   
                   
                   
                 CD34 +  hematopoetic 
                   
               
               
                   
                   
                   
                   
                 progenitors, 
                   
               
               
                   
                   
                   
                   
                 keratinocytes, mast cells 
                   
               
               
                   
                   
                   
                   
                 CCR5: T cells, 
                   
               
               
                   
                   
                   
                   
                 macrophages, dendritic 
                   
               
               
                   
                   
                   
                   
                 cells, eosinophils and 
                   
               
               
                   
                   
                   
                   
                 microglia 
                   
               
               
                 CCL4 
                 CCL4 
                 MIP-1 beta, 
                 macrophages, 
                 CCR1: lymphocytes, 
                 migration and 
               
               
                   
                   
                 AT744.1, 
                 dendritic cells 
                 monocytes, airway 
                 adhesion of 
               
               
                   
                   
                 ACT-2, G-26, 
                   
                 smooth muscle cells 
                 lymphocytes, 
               
               
                   
                   
                 HC21, H400, 
                   
                 CCR5: T cells, 
                 regulatory T 
               
               
                   
                   
                 MAD-5,  
                   
                 macrophages, dendritic 
                 cells, NK cells, 
               
               
                   
                   
                 LAG-1 
                   
                 cells, eosinophils and 
                 monocyrtes 
               
               
                   
                   
                   
                   
                 microglia 
                   
               
               
                   
                   
                   
                   
                 CCR8: natural killer 
                   
               
               
                   
                   
                   
                   
                 cells, monocytes and 
                   
               
               
                   
                   
                   
                   
                 lymphocytes 
                   
               
               
                   
                   
                   
                   
                 D6: lymphocytes, 
                   
               
               
                   
                   
                   
                   
                 lymphatic endothelial 
                   
               
               
                   
                   
                   
                   
                 cells, macrophages 
                   
               
               
                 CCL4L1 
                 CCL4L1 
                 AT744.2 
                 macrophages, 
                 CCR1: lymphocytes, 
                 CCR1 and 
               
               
                   
                   
                   
                 dendritic cells 
                 monocytes, airway 
                 CCR5 
               
               
                   
                   
                   
                   
                 smooth muscle cells 
                 expressing 
               
               
                   
                   
                   
                   
                 CCR5: T cells, 
                 cells 
               
               
                   
                   
                   
                   
                 macrophages, dendritic 
                   
               
               
                   
                   
                   
                   
                 cells, eosinophils and 
                   
               
               
                   
                   
                   
                   
                 microglia 
                   
               
               
                 CCL4L2 
                 CCL4L2 
                   
                 macrophages, 
                 CCR1: lymphocytes, 
                 CCR1 and 
               
               
                   
                   
                   
                 dendritic cells 
                 monocytes, airway 
                 CCR5 
               
               
                   
                   
                   
                   
                 smooth muscle cells 
                 expressing 
               
               
                   
                   
                   
                   
                 CCR5: T cells, 
                 cells 
               
               
                   
                   
                   
                   
                 macrophages, dendritic 
                   
               
               
                   
                   
                   
                   
                 cells, eosinophils and 
                   
               
               
                   
                   
                   
                   
                 microglia 
                   
               
               
                 CCL5 
                 CCL5 
                 RANTES 
                 T cells, 
                 CCR1: lymphocytes, 
                 migration of 
               
               
                   
                   
                   
                 macrophages, 
                 monocytes, airway 
                 monocytes, 
               
               
                   
                   
                   
                 platelets, synovial 
                 smooth muscle cells 
                 memory T 
               
               
                   
                   
                   
                 fibroblasts, tubular 
                 CCR3: eosinophils, 
                 helper cells and 
               
               
                   
                   
                   
                 epithelium, certain 
                 basophils, Th2 cells, 
                 eosinophils, 
               
               
                   
                   
                   
                 types of tumor cells 
                 CD34 +  hematopoetic 
                 causes the 
               
               
                   
                   
                   
                   
                 progenitors, 
                 release of 
               
               
                   
                   
                   
                   
                 keratinocytes, mast cells 
                 histamine from 
               
               
                   
                   
                   
                   
                 CCR4: lymphocytes 
                 basophils and 
               
               
                   
                   
                   
                   
                 CCR5: T cells, 
                 activates 
               
               
                   
                   
                   
                   
                 macrophages, dendritic 
                 eosinophils 
               
               
                   
                   
                   
                   
                 cells, eosinophils and 
                   
               
               
                   
                   
                   
                   
                 microglia 
                   
               
               
                   
                   
                   
                   
                 D6: lymphocytes, 
                   
               
               
                   
                   
                   
                   
                 lymphatic endothelial 
                   
               
               
                   
                   
                   
                   
                 cells, macrophages 
                   
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                   
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CCL7 
                 CCL7 
                 MCP-3 
                 macrophages, 
                 CCR1: lymphocytes, 
                 migration of 
               
               
                   
                   
                   
                 certain types of 
                 monocytes, airway 
                 monocytes, 
               
               
                   
                   
                   
                 tumor cells 
                 smooth muscle cells 
                 activation of 
               
               
                   
                   
                   
                   
                 CCR2: monocytes 
                 macrophages 
               
               
                   
                   
                   
                   
                 CCR3: eosinophils, 
                   
               
               
                   
                   
                   
                   
                 basophils, Th2 cells, 
                   
               
               
                   
                   
                   
                   
                 CD34 +  hematopoetic 
                   
               
               
                   
                   
                   
                   
                 progenitors, 
                   
               
               
                   
                   
                   
                   
                 keratinocytes, mast cells 
                   
               
               
                   
                   
                   
                   
                 D6: lymphocytes, 
                   
               
               
                   
                   
                   
                   
                 lymphatic endothelial 
                   
               
               
                   
                   
                   
                   
                 cells, macrophages 
                   
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                   
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CCL8 
                 CCL8 
                 MCP-2,  
                 fibroblasts, 
                 CCR1: lymphocytes, 
                 migration of 
               
               
                   
                   
                 HC14 
                 endothelial cells 
                 monocytes, airway 
                 monocytes, 
               
               
                   
                   
                   
                   
                 smooth muscle cells 
                 lymphocytes, 
               
               
                   
                   
                   
                   
                 CCR2: monocytes 
                 basophils and 
               
               
                   
                   
                   
                   
                 CCR3: eosinophils, 
                 eosinophils 
               
               
                   
                   
                   
                   
                 basophils, Th2 cells, 
                   
               
               
                   
                   
                   
                   
                 CD34 +  hematopoetic 
                   
               
               
                   
                   
                   
                   
                 progenitors, 
                   
               
               
                   
                   
                   
                   
                 keratinocytes, mast cells 
                   
               
               
                   
                   
                   
                   
                 CCR5: T cells, 
                   
               
               
                   
                   
                   
                   
                 macrophages, dendritic 
                   
               
               
                   
                   
                   
                   
                 cells, eosinophils and 
                   
               
               
                   
                   
                   
                   
                 microglia 
                   
               
               
                   
                   
                   
                   
                 CCR11: unkown 
                   
               
               
                   
                   
                   
                   
                 D6: lymphocytes, 
                   
               
               
                   
                   
                   
                   
                 lymphatic endothelial 
                   
               
               
                   
                   
                   
                   
                 cells, macrophages 
                   
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                   
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CCL11 
                 CCL11 
                 Eotaxin 
                 lung epithelial cells, 
                 CCR3: eosinophils, 
                 migration and 
               
               
                   
                   
                   
                 pleural mesothelial 
                 basophils, Th2 cells, 
                 activation of 
               
               
                   
                   
                   
                 cells, bronchial 
                 CD34 +  hematopoetic 
                 inflammatory 
               
               
                   
                   
                   
                 airway epithelial 
                 progenitors, 
                 leukocytes, 
               
               
                   
                   
                   
                 cells, smooth 
                 keratinocytes, mast cells 
                 particularly 
               
               
                   
                   
                   
                 muscle cells 
                 CCR5: T cells, 
                 eosinophils 
               
               
                   
                   
                   
                   
                 macrophages, dendritic 
                   
               
               
                   
                   
                   
                   
                 cells, eosinophils and 
                   
               
               
                   
                   
                   
                   
                 microglia 
                   
               
               
                   
                   
                   
                   
                 D6: lymphocytes, 
                   
               
               
                   
                   
                   
                   
                 lymphatic endothelial 
                   
               
               
                   
                   
                   
                   
                 cells, macrophages 
                   
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                   
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CCL12 
                   
                   
                 stromal cells in lung 
                 CCR2: monocytes 
                 migration and 
               
               
                   
                   
                   
                 and secondary 
                   
                 activation of 
               
               
                   
                   
                   
                 lymphoid organs 
                   
                 monocytes 
               
               
                 CCL13 
                 CCL13 
                 MCP-4, CK 
                 synovial fibroblasts, 
                 CCR1: lymphocytes, 
                 migration of 
               
               
                   
                   
                 beta 10, 
                 chondrocytes 
                 monocytes, airway 
                 eosinophils, 
               
               
                   
                   
                 NCC-1 
                   
                 smooth muscle cells 
                 monocytes and 
               
               
                   
                   
                   
                   
                 CCR2: monocytes 
                 T lymphocytes 
               
               
                   
                   
                   
                   
                 CCR3: eosinophils, 
                   
               
               
                   
                   
                   
                   
                 basophils, Th2 cells, 
                   
               
               
                   
                   
                   
                   
                 CD34 +  hematopoetic 
                   
               
               
                   
                   
                   
                   
                 progenitors, 
                   
               
               
                   
                   
                   
                   
                 keratinocytes, mast cells 
                   
               
               
                   
                   
                   
                   
                 CCR5: T cells, 
                   
               
               
                   
                   
                   
                   
                 macrophages, dendritic 
                   
               
               
                   
                   
                   
                   
                 cells, eosinophils and 
                   
               
               
                   
                   
                   
                   
                 microglia 
                   
               
               
                   
                   
                   
                   
                 CCR11: unkown 
                   
               
               
                   
                   
                   
                   
                 D6: lymphocytes, 
                   
               
               
                   
                   
                   
                   
                 lymphatic endothelial 
                   
               
               
                   
                   
                   
                   
                 cells, macrophages 
                   
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                   
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CCL14 
                 CCL14 
                 HCC-1, 
                 spleen, bone 
                 CCR1: lymphocytes, 
                 activation of 
               
               
                   
                   
                 MCIF, CK 
                 marrow, liver, 
                 monocytes, airway 
                 monocytes 
               
               
                   
                   
                 beta 1, NCC- 
                 muscle and gut 
                 smooth muscle cells 
                   
               
               
                   
                   
                 2 
                   
                 CCR3: eosinophils, 
                   
               
               
                   
                   
                   
                   
                 basophils, Th2 cells, 
                   
               
               
                   
                   
                   
                   
                 CD34 +  hematopoetic 
                   
               
               
                   
                   
                   
                   
                 progenitors, 
                   
               
               
                   
                   
                   
                   
                 keratinocytes, mast cells 
                   
               
               
                   
                   
                   
                   
                 CCR5: T cells, 
                   
               
               
                   
                   
                   
                   
                 macrophages, dendritic 
                   
               
               
                   
                   
                   
                   
                 cells, eosinophils and 
                   
               
               
                   
                   
                   
                   
                 microglia 
                   
               
               
                   
                   
                   
                   
                 D6: lymphocytes, 
                   
               
               
                   
                   
                   
                   
                 lymphatic endothelial 
                   
               
               
                   
                   
                   
                   
                 cells, macrophages 
                   
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                   
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CCL15 
                 CCL15 
                 MIP-1 delta, 
                 airway smooth 
                 CCR1: lymphocytes, 
                 migration of 
               
               
                   
                   
                 LKN-1, HCC- 
                 muscle cells, lung 
                 monocytes, airway 
                 monocytes and 
               
               
                   
                   
                 2, MIP-5, 
                 leukocytes, alveolar 
                 smooth muscle cells 
                 eosinophils, 
               
               
                   
                   
                 NCC-3 
                 macrophages, 
                 CCR3: eosinophils, 
                 proliferation of 
               
               
                   
                   
                   
                 basophils 
                 basophils, Th2 cells, 
                 CD34 myeloid 
               
               
                   
                   
                   
                   
                 CD34 +  hematopoetic 
                 progenitor cells 
               
               
                   
                   
                   
                   
                 progenitors, 
                   
               
               
                   
                   
                   
                   
                 keratinocytes, mast cells 
                   
               
               
                 CCL16 
                 CCL16 
                 HCC-4, LEC, 
                 liver, thymus, and 
                 CCR1: lymphocytes, 
                 migration of 
               
               
                   
                   
                 ILINCK, 
                 spleen 
                 monocytes, airway 
                 lymphocytes 
               
               
                   
                   
                 NCC-4, LMC, 
                   
                 smooth muscle cells 
                 and monocytes 
               
               
                   
                   
                 CK beta 12 
                   
                 CCR2: monocytes 
                   
               
               
                   
                   
                   
                   
                 CCR5: T cells, 
                   
               
               
                   
                   
                   
                   
                 macrophages, dendritic 
                   
               
               
                   
                   
                   
                   
                 cells, eosinophils and 
                   
               
               
                   
                   
                   
                   
                 microglia 
                   
               
               
                   
                   
                   
                   
                 CCR8: natural killer 
                   
               
               
                   
                   
                   
                   
                 cells, monocytes and 
                   
               
               
                   
                   
                   
                   
                 lymphocytes 
                   
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                   
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                   
                   
                   
                   
                 H4: bone marrow, 
                   
               
               
                   
                   
                   
                   
                 eosinophils, T-cells, 
                   
               
               
                   
                   
                   
                   
                 dendritic cells, 
                   
               
               
                   
                   
                   
                   
                 monocytes, mast cells, 
                   
               
               
                   
                   
                   
                   
                 neutrophil 
                   
               
               
                 CCL17 
                 CCL17 
                 TARC, 
                 constitutively 
                 CCR4: lymphocytes 
                 Migration and 
               
               
                   
                   
                 ABCD-2 
                 expressed in 
                 CCR8: natural killer 
                 activation of T 
               
               
                   
                   
                   
                 thymus, dendritic 
                 cells, monocytes and 
                 cells 
               
               
                   
                   
                   
                 cells, keratinocytes 
                 lymphocytes 
                   
               
               
                   
                   
                   
                   
                 D6: lymphocytes, 
                   
               
               
                   
                   
                   
                   
                 lymphatic endothelial 
                   
               
               
                   
                   
                   
                   
                 cells, macrophages 
                   
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                   
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CCL18 
                 CCL18 
                 PARC, DC- 
                 dendritic cells, 
                 CCR8: natural killer 
                 migration of 
               
               
                   
                   
                 CK1, AMAC- 
                 monocytes, and 
                 cells, monocytes and 
                 naive and 
               
               
                   
                   
                 1, CK beta 7, 
                 macrophages 
                 lymphocytes 
                 regulatory 
               
               
                   
                   
                 MIP-4 
                   
                 PITPNM3: breast cancer 
                 lymphocytes, 
               
               
                   
                   
                   
                   
                 cells 
                 dendritic cells 
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                   
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CCL19 
                 CCL19 
                 MIP-3 beta, 
                 fibroblastic reticular 
                 CCR7: lymphocytes 
                 migration of 
               
               
                   
                   
                 ELC, Exodus- 
                 cells, dendritic cells  
                 (mainly naive and 
                 naive and 
               
               
                   
                   
                 3, CK beta 11 
                   
                 memory), mature 
                 memory 
               
               
                   
                   
                   
                   
                 dendritic cells 
                 lymphocytes 
               
               
                   
                   
                   
                   
                 CCR11: unkown 
                 and mature 
               
               
                   
                   
                   
                   
                 CCRL2: neutrophils, 
                 dendritic cells 
               
               
                   
                   
                   
                   
                 monocytes 
                   
               
               
                 CCL20 
                 CCL20 
                 MIP-3 alpha, 
                 epidermis 
                 CCR6: immature 
                 migration of 
               
               
                   
                   
                 LARC, 
                 (keratinocytes), 
                 dendritic cells and 
                 lymphocytes, 
               
               
                   
                   
                 Exodus-1, 
                 lymphocytes 
                 memory T cells 
                 DCs and 
               
               
                   
                   
                 ST38, CK 
                   
                   
                 neutrophils 
               
               
                   
                   
                 beta 4 
                   
                   
                   
               
               
                 CCL21 
                 CCL21 
                 6Ckine, 
                 Stromal cells, 
                 CCR7: lymphocytes 
                 migration of 
               
               
                   
                   
                 Exodus-2, 
                 lymphatic 
                 (mainly naive and 
                 lymphocytes 
               
               
                   
                   
                 SLC, TCA-4, 
                 endothelial cells, 
                 memory), mature 
                 homing to 
               
               
                   
                   
                 CK beta 9 
                 fibroblastic reticular  
                 dendritic cells  
                 secondary 
               
               
                   
                   
                   
                 cells, dendritic cells  
                 CCR11: unkown 
                 lymphoid 
               
               
                   
                   
                   
                   
                   
                 organs, 
               
               
                   
                   
                   
                   
                   
                 induces 
               
               
                   
                   
                   
                   
                   
                 integrin- 
               
               
                   
                   
                   
                   
                   
                 mediated 
               
               
                   
                   
                   
                   
                   
                 lymphocyte 
               
               
                   
                   
                   
                   
                   
                 adhesion 
               
               
                 CCL22 
                 CCL22 
                 MDC 
                 Macrophages 
                 CCR4: lymphocytes 
                 migration of NK 
               
               
                   
                   
                   
                   
                 D6: lymphocytes, 
                 cells, 
               
               
                   
                   
                   
                   
                 lymphatic endothelial 
                 chronically 
               
               
                   
                   
                   
                   
                 cells, macrophages 
                 activated T 
               
               
                   
                   
                   
                   
                   
                 cells, 
               
               
                   
                   
                   
                   
                   
                 monocytes and 
               
               
                   
                   
                   
                   
                   
                 DCs 
               
               
                 CCL23 
                 CCL23 
                 MPIF-1, CK 
                 Monocytes 
                 CCR1: lymphocytes, 
                 migration of 
               
               
                   
                   
                 beta 8, CK 
                   
                 monocytes 
                 monocytes, 
               
               
                   
                   
                 beta 8-1, 
                   
                 FPRL-1: monocytes, 
                 resting T cells 
               
               
                   
                   
                 MIP-3 
                   
                 mast cells 
                 and neutrophils 
               
               
                 CCL24 
                 CCL24 
                 Eotaxin-2, 
                 lung tissue 
                 CCR3: eosinophils, 
                 migration of 
               
               
                   
                   
                 MPIF-2, CK 
                   
                 basophils, Th2 cells, 
                 basophils 
               
               
                   
                   
                 beta 6 
                   
                 CD34 +  hematopoetic 
                   
               
               
                   
                   
                   
                   
                 progenitors, 
                   
               
               
                   
                   
                   
                   
                 keratinocytes, mast cells 
                   
               
               
                 CCL25 
                 CCL25 
                 TECK, CK 
                 thymic dendritic cells 
                 CCR9: T lymphocytes of 
                 migration of 
               
               
                   
                   
                 beta 15 
                 and mucosal 
                 small intestine 
                 dendritic cells, 
               
               
                   
                   
                   
                 epithelial cells 
                   
                 thymocytes and 
               
               
                   
                   
                   
                   
                   
                 activated 
               
               
                   
                   
                   
                   
                   
                 macrophages 
               
               
                 CCL26 
                 CCL26 
                 Eotaxin-3, 
                 heart, lung and 
                 CCR3: eosinophils, 
                 migration of 
               
               
                   
                   
                 MIP-4 alpha, 
                 ovary and in 
                 basophils, Th2 cells, 
                 eosinophils and 
               
               
                   
                   
                 IMAC, TSC-1 
                 endothelial cells 
                 CD34 +  hematopoetic 
                 basophils 
               
               
                   
                   
                   
                 stimulated with IL4 
                 progenitors, 
                   
               
               
                   
                   
                   
                   
                 keratinocytes, mast cells 
                   
               
               
                   
                   
                   
                   
                 CX3CR1: lymphocytes, 
                   
               
               
                   
                   
                   
                   
                 monocytes 
                   
               
               
                 CCL27 
                 CCL27 
                 CTACK, ILC, 
                 Keratinocytes 
                 CCR10: melanocytes, 
                 migration of 
               
               
                   
                   
                 PESKY, 
                   
                 plasma cells and skin- 
                 memory T cells 
               
               
                   
                   
                 ESKINE 
                   
                 homing T cells 
                   
               
               
                 CCL28 
                 CCL28 
                 MEC 
                 columnar epithelial 
                 CCR3: eosinophils, 
                 migration of 
               
               
                   
                   
                   
                 cells in the gut, lung, 
                 basophils, Th2 T cells, 
                 lymphocytes 
               
               
                   
                   
                   
                 breast and the 
                 CD34 +  hematopoetic 
                 and eosinophils 
               
               
                   
                   
                   
                 salivary glands 
                 progenitors, 
                   
               
               
                   
                   
                   
                   
                 keratinocytes, mast cells 
                   
               
               
                   
                   
                   
                   
                 CCR10: melanocytes, 
                   
               
               
                   
                   
                   
                   
                 plasma cells and skin- 
                   
               
               
                   
                   
                   
                   
                 homing T cells 
                   
               
               
                 CXC Family 
                   
                   
                   
                   
                   
               
               
                 CXCL1 
                 CXCL1 
                 GRO alpha, 
                 mammary, 
                 CXCR2 (IL8RB): 
                 migration of 
               
               
                   
                   
                 MGSA, 
                 fibroblasts, 
                 neutrophils 
                 neutrophils 
               
               
                   
                   
                 GRO1, NAP- 
                 mammary epithelial 
                 DARC: erytrocytes, 
                   
               
               
                   
                   
                 3 
                 cells, endothelial 
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                 cells, activated, 
                 cells 
                   
               
               
                   
                   
                   
                 monocytes, 
                   
                   
               
               
                   
                   
                   
                 macrophages and 
                   
                   
               
               
                   
                   
                   
                 neutrophils 
                   
                   
               
               
                 CXCL2 
                 CXCL2 
                 GRO beta, 
                 monocytes, 
                 CXCR2 (IL8RB): 
                 migration and 
               
               
                   
                   
                 MIP-2 alpha, 
                 macrophages 
                 neutrophils 
                 activation of 
               
               
                   
                   
                 GRO2 
                   
                 DARC: erytrocytes,  
                 neutrophils, 
               
               
                   
                   
                   
                   
                 endothelial and epithelial  
                 basophils, 
               
               
                   
                   
                   
                   
                 cells 
                 hematopoietic 
               
               
                   
                   
                   
                   
                   
                 stem cells 
               
               
                 CXCL3 
                 CXCL3 
                 GRO gamma, 
                 smooth muscle 
                 CXCR2 (IL8RB): 
                 migration and 
               
               
                   
                   
                 MIP-2 beta, 
                 cells, epithelial cells 
                 neutrophils 
                 activation of 
               
               
                   
                   
                 GRO3 
                   
                 DARC: erytrocytes,  
                 neutrophils 
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CXCL4 
                 PF4 
                 PF4 
                 activated platelets, 
                 CXCR3 (CD183b): T 
                 migration of 
               
               
                   
                   
                   
                 megakaryocytes, 
                 cells, NK cells 
                 neutrophils and 
               
               
                   
                   
                   
                 leukocytes, 
                 CXCR3-B: T cells, NK 
                 fibroblasts, 
               
               
                   
                   
                   
                 endothelial cells 
                 cells 
                 inhibiting 
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                 endothelial cell 
               
               
                   
                   
                   
                   
                 endothelial and epithelial  
                 proliferation 
               
               
                   
                   
                   
                   
                 cells 
                 and chemotaxis 
               
               
                 CXCL4L1 
                 PF4V1 
                 PF4V1 
                 smooth muscle 
                 CXCR3 (CD183b): T 
                 inhibiting 
               
               
                   
                   
                   
                 cells, T cells, and 
                 cells, NK cells 
                 endothelial cell 
               
               
                   
                   
                   
                 platelets 
                 CXCR3-B: T cells, NK 
                 proliferation 
               
               
                   
                   
                   
                   
                 cells 
                 and chemotaxis 
               
               
                 CXCL5 
                 CXCL5 
                 ENA-78 
                 fibroblasts, epithelial 
                 CXCR2 (IL8RB): 
                 migration and 
               
               
                   
                   
                   
                 cells, eosinophils 
                 neutrophils 
                 activation of 
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                 neutrophils 
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CXCL6 
                 CXCL6 
                 GCP-2 
                 fibroblasts, epithelial 
                 CXCR1 (IL8RA): 
                 migration of 
               
               
                   
                   
                   
                 cells 
                 neutrophils 
                 neutrophils 
               
               
                   
                   
                   
                   
                 CXCR2 (IL8RB): 
                   
               
               
                   
                   
                   
                   
                 neutrophils 
                   
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                   
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CXCL7 
                 PPBP 
                 NAP-2, 
                 activated platelets 
                 CXCR1 (IL8RA): 
                 migration of 
               
               
                   
                   
                 CTAPIII, 
                   
                 neutrophils 
                 neutrophils 
               
               
                   
                   
                 beta-TG 
                   
                 CXCR2 (IL8RB): 
                   
               
               
                   
                   
                   
                   
                 neutrophils 
                   
               
               
                 CXCL8 
                 IL8 
                 IL-8,  
                 macrophages, 
                 CXCR1 (IL8RA): 
                 migration of 
               
               
                   
                   
                 NAP-1, 
                 epithelial cells, 
                 neutrophils 
                 neutrophils, 
               
               
                   
                   
                 MDNCF, 
                 airway smooth 
                 CXCR2 (IL8RB): 
                 basophils, and 
               
               
                   
                   
                 GCP-1 
                 muscle cells, 
                 neutrophils 
                 T-cells, and 
               
               
                   
                   
                   
                 endothelial cells 
                 DARC: erytrocytes, 
                 angiogenic 
               
               
                   
                   
                   
                   
                 endothelial and epithelial  
                 factor 
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CXCL9 
                 CXCL9 
                 MIG,  
                 monocytes, 
                 CXCR3 (CD183b): T 
                 migration of 
               
               
                   
                   
                 CRG-10 
                 macrophages and 
                 cells, NK cells 
                 Th1 
               
               
                   
                   
                   
                 endothelial cells 
                 CXCR3-B: T cells, NK 
                 lymphocytes, 
               
               
                   
                   
                   
                   
                 cells 
                 angiogenic 
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                 factor 
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CXCL10 
                 CXCL10 
                 IP-10 
                 neutrophils, 
                 CXCR3 (CD183b): T 
                 migration of 
               
               
                   
                   
                   
                 hepatocytes, 
                 cells, NK cells 
                 CD4 +  T cells 
               
               
                   
                   
                   
                 endothelial cells and 
                 CXCR3-B T cells, NK 
                   
               
               
                   
                   
                   
                 keratinocytes 
                 cells 
                   
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                   
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CXCL11 
                 CXCL11 
                 I-TAC,  
                 peripheral blood 
                 CXCR3 (CD183b): T 
                 migration of 
               
               
                   
                   
                 beta-R1, 
                 leukocytes, 
                 cells, NK cells 
                 interleukin- 
               
               
                   
                   
                 H174,  
                 pancreas and liver 
                 CXCR7 (ACKR3): tumor 
                 activated T 
               
               
                   
                   
                 IP-9 
                 astrocytes and at 
                 cells and tumor- 
                 cells but not 
               
               
                   
                   
                   
                 moderate levels in 
                 associated blood 
                 unstimulated T 
               
               
                   
                   
                   
                 thymus, spleen and 
                 endothelium 
                 cells, 
               
               
                   
                   
                   
                 lung 
                 DARC: erytrocytes, 
                 neutrophils or 
               
               
                   
                   
                   
                   
                 endothelial and epithelial  
                 monocytes. 
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CXCL12 
                 CXCL12 
                 SDF-1,  
                 ubiquitously 
                 CXCR4: brain, heart, 
                 migration of 
               
               
                   
                   
                 PBSF 
                 expressed in many 
                 lymphocytes, HSCs,  
                 lymphocytes 
               
               
                   
                   
                   
                 tissues and cell 
                 blood endothelial cells 
                 and 
               
               
                   
                   
                   
                 types 
                 and umbilical cord 
                 hepatopoietic 
               
               
                   
                   
                   
                   
                 endothelial cell 
                 stem cells, 
               
               
                   
                   
                   
                   
                 CXCR7 (ACKR3): tumor 
                 angiogenic 
               
               
                   
                   
                   
                   
                 cells and tumor- 
                 factor 
               
               
                   
                   
                   
                   
                 associated blood 
                   
               
               
                   
                   
                   
                   
                 endothelium 
                   
               
               
                 CXCL13 
                 CXCL13 
                 BCA-1,  
                 follicles of the 
                 CXCR3 (CD183b): T 
                 migration of B 
               
               
                   
                   
                 BLC 
                 spleen, lymph 
                 cells, NK cells 
                 cells 
               
               
                   
                   
                   
                 nodes, and Peyer&#39;s 
                 CXCR5: Burkitt&#39;s 
                   
               
               
                   
                   
                   
                 patches 
                 lymphoma, lymph node 
                   
               
               
                   
                   
                   
                   
                 follicules, spleen 
                   
               
               
                   
                   
                   
                   
                 DARC: erytrocytes, 
                   
               
               
                   
                   
                   
                   
                 endothelial and epithelial 
                   
               
               
                   
                   
                   
                   
                 cells 
                   
               
               
                 CXCL14 
                 CXCL14 
                 BRAK,  
                 Fibroblasts 
                 unknown 
                 migration of 
               
               
                   
                   
                 BMAC 
                   
                   
                 monocytes, NK 
               
               
                   
                   
                   
                   
                   
                 cells, DCs 
               
               
                 CXCL16 
                 CXCL16 
                 SR-PSOX 
                 DCs 
                 CXCR6: T cells 
                 migration of 
               
               
                   
                   
                   
                   
                   
                 several subsets 
               
               
                   
                   
                   
                   
                   
                 of T cells and 
               
               
                   
                   
                   
                   
                   
                 NKT cells 
               
               
                 CXCL17 
                 CXCL17 
                 DMC,  
                 Lung and tumor 
                 unknown 
                 migration of 
               
               
                   
                   
                 VCC-1 
                 tissue 
                   
                 DCs and 
               
               
                   
                   
                   
                   
                   
                 monocytes 
               
               
                   
               
            
           
         
       
     
                     TABLE 6                  EXAMPLES OF HUMAN IMMUNE CELL TRAFFICKING MOLECULES                                 Trafficking molecule               Trafficking   expressing or       Function in the extravasation       molecule   presenting cells   Leukocyte ligand   cascade                                     P-selectin   Blood endothelial cell   PSGL-1, L-selectin,   Tethering/Rolling during               CD44   extravasation cascade       E-selectin   Blood endothelial cell   Glycoprotein,   Tethering/Rolling during               glycolipid, PSGL-1   extravasation cascade       PNAd   Blood endothelial cell   L-selectin   Tethering/Rolling during                   extravasation cascade       MAdCAM   Blood endothelial cell   L-selectin, integrins   Tethering/Rolling, arrest during                   extravasation cascade       VCAM-1   Blood endothelial cell   Integrins (e.g. VLA-   Tethering/Rolling, arrest during               4)   extravasation cascade       Chemokines   Blood endothelial cell   GPCRs   Integrin activation, allowing binding of                   cell adhesion molecules and arrest       ICAM-1   Blood endothelial cell   Integrins (e.g. LFA-   Arrest during extravasation cascade               1, Mac-1)           ICAM-2   Blood endothelial cell   Integrins (e.g. LFA-   Arrest during extravasation cascade               1, Mac-1)           PECAM1   Blood endothelial cell   Integrins (e.g. alpha   Transmigration       (CD31)       v beta 3), PECAM1           JAM-A/-B/-   Blood endothelial cell   Integrins (e.g. LFA-   Transmigration       C       1, Mac-1, VLA-4)           ESAM   Blood endothelial cell   unknown   Transmigration       CD99   Blood endothelial cell   CD99   Transmigration       CD99L2   Blood endothelial cell   possibly CD99L   Transmigration       VE-cadherin   Blood endothelial cell   None   Transmigration       PVR   Blood endothelial cell   DNAM1   Transmigration       S1P   Lymphatic   S1P receptor 1   Entry into afferent and efferent           endothelial cell   (S1P1)   lymphatics (in peripheral or SLOs                   respectively)                    
Cancer
 
     The methods described herein can be used to treat cancer in a subject by administering to the subject an effective amount of a serotonin receptor inhibitor, e.g., a serotonin receptor inhibitor described herein. The method may include administering locally (e.g., intratumorally) to the subject a serotonin receptor inhibitor described herein in a dose (e.g., effective amount) and for a time sufficient to treat the cancer. 
     The methods described herein can also be used to potentiate or increase an immune response in a subject in need thereof, e.g., an anti-tumor immune response. For example, the subject has cancer, such as a cancer described herein. The methods described herein can also include a step of selecting a subject in need of potentiating an immune response, e.g., selecting a subject who has cancer or is at risk of developing cancer. 
     The serotonin receptor inhibitor may inhibit proliferation or disrupt the function of non-neural cells that promote cancer growth that are associated with the cancer, e.g., the method includes administering to the subject an effective amount of a serotonin receptor inhibitor for a time sufficient to inhibit proliferation or disrupt the function of non-neural cells that promote cancer growth that are associated with the cancer. Non-neural cells that promote cancer growth that are associated with the cancer include malignant cancer cells, malignant cancer cells in necrotic and hypoxic areas, M2 macrophages, tumor associated macrophages, T regulatory cells, myeloid derived suppressor cells, adipocytes, B10 cells, Breg cells, endothelial cells, cancer associated fibroblasts, fibroblasts, mesenchymal stem cells, red blood cells, or extracellular matrix. The proliferation of non-neural cells that promote cancer growth that are associated with the cancer may be decreased in the subject at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, compared to before the administration. The proliferation of non-neural cells that promote cancer growth that are associated with the cancer can be decreased in the subject between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%. 
     The serotonin receptor inhibitor may promote proliferation or enhance the function of non-neural cells that disrupt cancer growth that are associated with the cancer, e.g., the method includes administering to the subject an effective amount of a serotonin receptor inhibitor for a time sufficient to promote proliferation or enhance the function of non-neural cells that disrupt cancer growth that are associated with the cancer. Non-neural cells that disrupt cancer growth that are associated with the cancer include NK cells, NKT cells, M1 macrophages, Th1 helper cells, Th2 helper cells, CD8 cytotoxic T cells, Th17 cells, tumor associated neutrophils, terminally differentiated myeloid dendritic cells, T lymphocytes, B lymphocytes, lymphatic endothelial cells, pericytes, dendritic cells, mesenchymal stem cells, red blood cells, or extracellular matrix. The proliferation of non-neural cells that disrupt cancer growth that are associated with the cancer may be increased in the subject at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, compared to before the administration. The proliferation of non-neural cells that disrupt cancer growth that are associated with the cancer can be increased in the subject between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%. 
     The serotonin receptor inhibitor can be administered in an amount sufficient to treat cancer. For example, the stroma associated with the tumor, e.g., fibroblasts, is disrupted such that an essential function, e.g., the production of matrix metalloproteases, is altered to inhibit tumor survival or promote tumor control. 
     The serotonin receptor inhibitor can have one or more of the following activities: (a) inhibits an immune checkpoint, (b) activates anti-tumor immune response, (c) activate tumor-specific T cells from draining lymph nodes, and/or (d) stimulates a neoantigen-specific immune response. The activity can be modulated as appropriate in the subject (e.g., a human subject or animal model) at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, compared to before the administration. The activity can be modulated as appropriate in the subject between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%. 
     The serotonin receptor inhibitor can treat cancer by increasing cancer cell death in a subject (e.g., a human subject or animal model) or in a cancer cell culture (e.g., a culture generated from a patient tumor sample, a cancer cell line, or a repository of patient samples). A serotonin receptor inhibitor can increase cancer cell death by at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more compared to before administration to a subject or cancer cell culture. A serotonin receptor inhibitor can increase cancer cell death in a subject or cancer cell culture between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%. 
     The serotonin receptor inhibitor can also act to inhibit cancer cell growth, proliferation, metastasis, migration, or invasion, e.g., the method includes administering to the subject (e.g., a human subject or animal model) or a cancer cell culture (e.g., a culture generated from a patient tumor sample, a cancer cell line, or a repository of patient samples) a serotonin receptor inhibitor in an amount (e.g., an effective amount) and for a time sufficient to inhibit cancer cell growth, proliferation, metastasis, migration, or invasion. Cancer cell growth, proliferation, metastasis, migration, or invasion can be decreased in the subject or cancer cell culture at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, compared to before the administration Cancer cell growth, proliferation, metastasis, migration, or invasion can be decreased in the subject or cancer cell culture between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%. 
     The serotonin receptor inhibitor can inhibit cancer cell invasion or metastasis along a nerve, e.g., the method includes administering to the subject (e.g., a human subject or animal model) a serotonin receptor inhibitor in an amount (e.g., an effective amount) and for a time sufficient to inhibit cancer cell invasion or metastasis along a nerve. The serotonin receptor inhibitor can decrease cancer cell invasion or metastasis along a nerve in the subject at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, compared to before the administration. The serotonin receptor inhibitor can decrease cancer cell invasion or metastasis along a nerve in the subject between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%. 
     The serotonin receptor inhibitor can also reduce the number of nerve fibers in the affected tissue or reduce the activity of peripheral nerve fibers in the affected tissue. For example, the method includes administering to the subject (e.g., a human subject or animal model) a serotonin receptor inhibitor in an amount (e.g., an effective amount) and for a time sufficient to reduce the number of nerve fibers in the affected tissue or reduce the activity of peripheral nerve fibers in the affected tissue. The affected tissue can be a tumor, a tumor micro-environment, lymph node, a lymphoid organ, or the bone marrow niche. The number of nerve fibers in the affected tissue or the activity of peripheral nerve fibers in the affected tissue can be decreased in the subject at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, compared to before the administration. The number of nerve fibers in the affected tissue or the activity of peripheral nerve fibers in the affected tissue can be decreased in the subject between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%. 
     The nerve fibers that are modulated can be part of the peripheral nervous system, e.g., a somatic nerve, an autonomic nerve, a sensory nerve, a cranial nerve, an optic nerve, an olfactory nerve, a sympathetic nerve, a parasympathetic nerve, a chemoreceptor, a photoreceptor, a mechanoreceptor, a thermoreceptor, a nociceptor, an efferent nerve fiber, or an afferent nerve fiber. 
     Cancer Types 
     In the methods described herein, the cancer or neoplasm may be any solid or liquid cancer and includes benign or malignant tumors, and hyperplasias, including gastrointestinal cancer (such as non-metastatic or metastatic colorectal cancer, pancreatic cancer, gastric cancer, esophageal cancer, hepatocellular cancer, cholangiocellular cancer, oral cancer, lip cancer); urogenital cancer (such as hormone sensitive or hormone refractory prostate cancer, renal cell cancer, bladder cancer, penile cancer); gynecological cancer (such as ovarian cancer, cervical cancer, endometrial cancer); lung cancer (such as small-cell lung cancer and non-small-cell lung cancer); head and neck cancer (e.g., head and neck squamous cell cancer); CNS cancer including malignant glioma, astrocytomas, retinoblastomas and brain metastases; malignant mesothelioma; non-metastatic or metastatic breast cancer (e.g., hormone refractory metastatic breast cancer); skin cancer (such as malignant melanoma, basal and squamous cell skin cancers, Merkel Cell Carcinoma, lymphoma of the skin, Kaposi Sarcoma); thyroid cancer; bone and soft tissue sarcoma; and hematologic neoplasias (such as multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, Hodgkin&#39;s lymphoma). 
     Additional cancers that can be treated according to the methods described herein include breast cancer, lung cancer, stomach cancer, colon cancer, liver cancer, renal cancer, colorectal cancer, prostate cancer, pancreatic cancer, cervical cancer, anal cancer, vulvar cancer, penile cancer, vaginal cancer, testicular cancer, pelvic cancer, thyroid cancer, uterine cancer, rectal cancer, brain cancer, head and neck cancer, esophageal cancer, bronchus cancer, gallbladder cancer, ovarian cancer, bladder cancer, oral cancer, oropharyngeal cancer, larynx cancer, biliary tract cancer, skin cancer, a cancer of the central nervous system, a cancer of the respiratory system, and a cancer of the urinary system. Examples of breast cancers include, but are not limited to, triple-negative breast cancer, triple-positive breast cancer, HER2-negative breast cancer, HER2-positive breast cancer, estrogen receptor-positive breast cancer, estrogen receptor-negative breast cancer, progesterone receptor-positive breast cancer, progesterone receptor-negative breast cancer, ductal carcinoma in situ (DCIS), invasive ductal carcinoma, invasive lobular carcinoma, inflammatory breast cancer, Paget disease of the nipple, and phyllodes tumor. 
     Other cancers that can be treated according to the methods described herein include leukemia (e.g., B-cell leukemia, T-cell leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic (lymphoblastic) leukemia (ALL), chronic lymphocytic leukemia (CLL), and erythroleukemia), sarcoma (e.g., angiosarcoma, chondrosarcoma, Ewing&#39;s sarcoma, fibrosarcoma, gastrointestinal stromal tumor, leiomyosarcoma, liposarcoma, malignant peripheral nerve sheath tumor, malignant fibrous cytoma, osteosarcoma, pleomorphic sarcoma, rhabdomyosarcoma, synovial sarcoma, vascular sarcoma, Kaposi&#39;s sarcoma, dermatofibrosarcoma, epithelioid sarcoma, leyomyosarcoma, and neurofibrosarcoma), carcinoma (e.g., basal cell carcinoma, large cell carcinoma, small cell carcinoma, non-small cell lung carcinoma, renal carcinoma, hepatocarcinoma, gastric carcinoma, choriocarcinoma, adenocarcinoma, hepatocellular carcinoma, giant (or oat) cell carcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastmic carcinoma, adrenocortical carcinoma, cholangiocarcinoma, Merkel cell carcinoma, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma), blastoma (e.g., hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma, pleuropulmonary blastoma, retinoblastoma, and glioblastoma multiforme), lymphoma (e.g., Hodgkin&#39;s lymphoma, non-Hodgkin&#39;s lymphoma, and Burkitt lymphoma), myeloma (e.g., multiple myeloma, plasmacytoma, localized myeloma, and extramedullary myeloma), melanoma (e.g., superficial spreading melanoma, nodular melanoma, lentigno maligna melanoma, acral lentiginous melanoma, and amelanotic melanoma), neuroma (e.g., ganglioneuroma, Pacinian neuroma, and acoustic neuroma), glioma (e.g., astrocytoma, oligoastrocytoma, ependymoma, brainstem glioma, optic nerve glioma, and oligoastrocytoma), pheochromocytoma, meningioma, malignant mesothelioma, and virally induced cancer. 
     In some embodiments, the cancer is a paraneoplastic cancer (e.g., a cancer that causes a paraneoplastic syndrome). Paraneoplastic syndromes are rare disorders that are triggered by an altered immune system response to a neoplasm, and are mediated by humoral factors such as hormones, cytokines, or auto-antibodies produced by the tumor. Symptoms of paraneoplastic syndrome may be endocrine, neuromuscular, or musculoskeletal, cardiovascular, cutaneous, hematologic, gastrointestinal, renal, or neurological. Paraneoplastic syndromes commonly present with lung, breast, and ovarian cancer and cancer of the lymphatic system (e.g., lymphoma). Paraneoplastic neurological disorders are disorders that affect the central or peripheral nervous system, and can include symptoms such as ataxia (difficulty with walking and balance), dizziness, nystagmus (rapid uncontrolled eye movements), difficulty swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech memory loss, vision problems, sleep disturbances, dementia, seizures, or sensory loss in the limbs. Breast, ovarian, and lung cancers are most commonly associated with paraneoplastic neurological disorders. Other common types of paraneoplastic syndromes include paraneoplastic cerebellar degeneration, paraneoplastic pemphigus, paraneoplastic autonomic neuropathy, paraneoplastic encephalomyelitis, and cancer-associated autoimmune retinopathy. 
     Endocrine paraneoplastic syndromes include Cushing syndrome (caused by ectopic ACTH), which is most commonly caused by small cell lung cancer, pancreatic carcinoma, neural tumors, or thymoma; SIADH (caused by antidiuretic hormone), which is most commonly caused by small cell lung cancer and CNS malignancies; hypercalcemia (caused by PTHrp, TGFα, TNF, or IL-1), which is most commonly caused by lung cancer, breast carcinoma, renal and bladder carcinoma, multiple myeloma, adult T cell leukemia/lymphoma, ovarian carcinoma, and squamous cell carcinoma (e.g., lung, head, neck, or esophagus carcinoma); hyperglycemia (caused by insulin insulin-like substance, or “big” IGF-II), which is most commonly caused by fibrosarcoma, mesenchymal sarcomas, insulinoma, and hepatocellular carcinoma; carcinoid syndrome (caused by serotonin or bradykinin), which is most commonly caused by bronchial adenoma, pancreatic carcinoma, and gastric carcinoma; and hyperaldosteronism (caused by aldosterone), which is most commonly caused by adrenal adenoma/Conn&#39;s syndrome, non-Hodgkin&#39;s lymphoma, ovarian carcinoma, and pulmonary cancer. 
     Neurological paraneoplastic syndromes include Lambert-Eaton myasthenic syndrome (LEMS), which is most commonly caused by small cell lung cancer; paraneoplastic cerebellar degeneration, which is most commonly caused by lung cancer, ovarian cancer, breast carcinoma, and Hodgkin&#39;s lymphoma; encephalomyelitis; limbic encephalitis, which is most commonly caused by small cell lung carcinoma; myasthenia gravis, which is most commonly caused by thymoma; brainstem encephalitis; opsoclonus myoclonus ataxia (caused by autoimmune reaction against Nova-1), which is most commonly caused by breast carcinoma, ovarian carcinoma, small cell lung carcinoma, and neuroblastoma; anti-NMDA receptor encephalitis (caused by autoimmune reaction against NMDAR subunits), which is most commonly caused by teratoma; and polymyositis, which is most commonly caused by lung cancer, bladder cancer, and non-Hodgkin&#39;s lymphoma. Mucotaneous paraneoplastic syndromes include acanthosis  nigricans , which is most commonly caused by gastric carcinoma, lung carcinoma, and uterine carcinoma; dermatomyositis, which is most commonly caused by bronchogenic carcinoma, breast carcinoma, ovarian cancer, pancreatic cancer, stomach cancer, colorectal cancer, and Non-Hodgkin&#39;s lymphoma; Leser-Trelat sign; necrolytic migratory erythema, which is most commonly caused by glucoganoma; Sweet&#39;s syndrome; 
     florid cutaneous papillomatosis; pyoderma gangrenosum; and acquired generalized hypertrichosis. 
     Hematological syndromes include granulocytosis (caused by G-CSF); polycythemia (caused by erythropoietin), which is commonly caused by renal carcinoma, cerebellar hemangioma, and heptatocellular carcinoma; Trousseau sign (caused by mucins), which is commonly caused by pancreatic carcinoma and bronchogenic carcinoma; nonbacterial thrombotic endocarditis, which is caused by advanced cancers; and anemia, which is most commonly caused by thymic neoplasms. Other paraneoplastic syndromes include membranous glomerular nephritis; neoplastic fever; Staffer syndrome, which is caused by renal cell carcinoma; and tumor-induced osteomalacia (caused by FGF23), which is caused by hemangiopericytoma and phosphaturic mesenchymal tumor. 
     In some embodiments, a subject is identified as having cancer after presenting with symptoms of a paraneoplastic syndrome. A common symptom of paraneoplastic syndrome is fever. Auto-antibodies directed against nervous system proteins are also frequently observed in patients with paraneoplastic syndromes, including anti-Hu, anti-Yo, anti-Ri, anti-amphiphysin, anti-CV2, anti-Ma2, anti-recoverin, anti-transducin, anti-carbonic anhydrase II, anti-arrestin, anti-GCAP1, anti-GCAP2, anti-HSP27, anti-Rab6A, and anti-PNR. Other symptoms that can be used to identify a patient with paraneoplastic cancer include ataxia, dizziness, nystagmus, difficulty swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech memory loss, vision loss, sleep disturbances, dementia, seizures, dysgeusia, cachexia, anemia, itching, or sensory loss in the limbs. In some embodiments, a patient presents with symptoms of paraneoplastic syndrome and is then identified as having cancer based on imaging tests (e.g., CT, MRI, or PET scans). 
     The cancer may be innervated, metastatic, non-metastatic cancer, or benign (e.g., a benign tumor). The cancer may be a primary tumor or a metastasized tumor. 
     In some embodiments, the cancer is a serotonin receptor-associated cancer (e.g., a cancer in associated with expression of one or more serotonin receptors in immune cells). 
     In some embodiments, the cancer is an immune cell-infiltrated cancer (e.g., a T cell infiltrated cancer, or a cancer with myeloid cell tumor infiltrate, e.g., a cancer infiltrated by T cells, dendritic cells, macrophages, monocytes, or myeloid derived suppressor cells). The immune cell-infiltrated cancer may be a “hot tumor” that contains T cells and expresses neoantigens. Cancers that are commonly considered “hot” include bladder cancer, head and neck cancer, kidney cancer, liver cancer, melanoma, non-small cell lung cancer, and microsatellite instability high cancer. The immune cell-infiltrated cancer may be a “cold tumor” that contains or is associated with suppressive immune cells, such as myeloid-derived suppressor cells and/or Tregs. Cancers that are immunologically “cold” typically do not respond to immunotherapy and include ovarian, prostate, and pancreatic cancer. A cancer in a subject can be identified as an immune cell-infiltrated cancer based on a biopsy, which can be evaluated for expression of immune cell markers (e.g., a marker listed in Table 3 and/or a marker described in Danaher et al., J Immunother Cancer 5:18, 2017) using standard methods, such as immunohistochemistry, flow cytometry, and expression profiling (e.g., RNAseq, microarray analysis, or a cancer immune profiling gene expression panel). In some embodiments, the cancer is a cancer that is treated with immunotherapy (e.g., melanoma, non-small cell lung cancer, kidney cancer, renal cell carcinoma, bladder cancer, head and neck cancer, Hodgkin&#39;s lymphoma, leukemia, urothelial carcinoma, gastric cancer, microsatellite instability-high cancer, colorectal cancer, and hepatocellular carcinoma). In some embodiments, the cancer is a cancer for which immunotherapy is not effective (e.g., a cancer that cannot be treated using immunotherapy or a cancer that did not respond to treatment with immunotherapy). 
     Subjects who can be treated with the methods disclosed herein include subjects who have had one or more tumors resected, received chemotherapy or other pharmacological treatment for the cancer, received radiation therapy, and/or received other therapy for the cancer. Subjects who can be treated with the methods disclosed herein include subjects that do not respond to immunotherapy. Subjects who have not previously been treated for cancer can also be treated with the methods disclosed herein. 
     Combination Therapies 
     A serotonin receptor inhibitor described herein can be administered in combination with a second therapeutic agent for treatment of cancer. In some embodiments, the second therapeutic agent is selected based on tumor type, tumor tissue of origin, tumor stage, or mutations in genes expressed by the tumor. 
     Checkpoint Inhibitors 
     One type of agent that can be administered in combination with a serotonin receptor inhibitor described herein is a checkpoint inhibitor. Checkpoint inhibitors can be broken down into at least 4 major categories: i) agents such as antibodies that block an inhibitory pathway directly on T cells or NK cells (e.g., PD-1 targeting antibodies such as nivolumab and pembrolizumab, antibodies targeting TIM-3, and antibodies targeting LAG-3, 2B4, CD160, A2aR, BTLA, CGEN-15049, or KIR), ii) agents such as antibodies that activate stimulatory pathways directly on T cells or NK cells (e.g., antibodies targeting OX40, GITR, or 4-1 BB), iii) agents such as antibodies that block a suppressive pathway on immune cells or rely on antibody-dependent cellular cytotoxicity to deplete suppressive populations of immune cells (e.g., CTLA-4 targeting antibodies such as ipilimumab, antibodies targeting VISTA, and antibodies targeting PD-L2, Gr1, or Ly6G), and iv) agents such as antibodies that block a suppressive pathway directly on cancer cells or that rely on antibody-dependent cellular cytotoxicity to enhance cytotoxicity to cancer cells (e.g., rituximab, antibodies targeting PD-L1, and antibodies targeting B7-H3, B7-H4, Gal-9, or MUC1). Such agents described herein can be designed and produced, e.g., by conventional methods known in the art (e.g., Templeton, Gene and Cell Therapy, 2015; Green and Sambrook, Molecular Cloning, 2012). 
     Chemotherapy 
     A second type of therapeutic agent that can be administered in combination with a serotonin receptor inhibitor described herein is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors,  vinca  alkaloids, epipodopyyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel; chloranbucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the first therapeutic agent described herein. Suitable dosing regimens of combination chemotherapies are known in the art. 
     Biologic Cancer Agents 
     Another type of therapeutic agent that can be administered in combination with a serotonin receptor inhibitor described herein is a therapeutic agent that is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In other embodiments the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab. In some embodiments the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer. Such agents include Rituximab; Daclizumab; Basiliximab; Palivizumab; Infliximab; Trastuzumab; Gemtuzumab ozogamicin; Alemtuzumab; Ibritumomab tiuxetan; Adalimumab; Omalizumab; Tositumomab-I-131; Efalizumab; Cetuximab; Bevacizumab; Natalizumab; Tocilizumab; Panitumumab; Ranibizumab; Eculizumab; Certolizumab pegol; Golimumab; Canakinumab; Ustekinumab; Ofatumumab; Denosumab; Motavizumab; Raxibacumab; Belimumab; Ipilimumab; Brentuximab Vedotin; Pertuzumab; Ado-trastuzumab emtansine; and Obinutuzumab. Also included are antibody-drug conjugates. Examples of biologic cancer agents that can be used in combination with serotonin receptor inhibitors described herein are shown in Table 7 below. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 APPROVED CANCER ANTIBODIES 
               
            
           
           
               
               
               
               
            
               
                 Antibody 
                 Company 
                 Antigen 
                 Indication 
               
               
                   
               
               
                 ado-trastuzumab 
                 Genentech 
                 HER2 
                 Metastatic breast cancer 
               
               
                 emtansine 
                   
                   
                   
               
               
                 alemtuzumab 
                 Genzyme 
                 CD52 
                 B-cell chronic lymphocytic leukemia 
               
               
                 atezolizumab 
                 Genentech 
                 PD-L1 
                 Urothelial carcinoma 
               
               
                   
                   
                   
                 Metastatic non-small cell lung cancer 
               
               
                 avelumab 
                 EMD Serono 
                 PD-L1 
                 Metastatic Merkel cell carcinoma 
               
               
                 bevacizumab 
                 Genentech 
                 VEGF 
                 Metastatic colorectal cancer 
               
               
                 blinatumomab 
                 Amgen 
                 CD19 
                 Precursor B-cell acute lymphoblastic 
               
               
                   
                   
                   
                 leukemia 
               
               
                 brentuximab 
                 Seattle Genetics 
                 CD30 
                 Hodgkin lymphoma 
               
               
                 vedotin 
                   
                   
                 Anaplastic large-cell lymphoma 
               
               
                 cetuximab 
                 ImClone Systems 
                 EGFR 
                 Metastatic colorectal carcinoma 
               
               
                 daratumumab 
                 Janssen Biotech 
                 CD38 
                 Multiple myeloma 
               
               
                 dinutuximab 
                 United Therapeutics 
                 GD2 
                 Pediatric high-risk neuroblastoma 
               
               
                 durvalumab 
                 AstraZeneca 
                 PD-L1 
                 Urothelial carcinoma 
               
               
                 elotuzumab 
                 Bristol-Myers 
                 SLAMF7 
                 Multiple myeloma 
               
               
                   
                 Squibb 
                   
                   
               
               
                 ibritumomab 
                 Spectrum 
                 CD20 
                 Relapsed or refractory low-grade, follicular, or 
               
               
                 tiuxetan 
                 Pharmaceuticals 
                   
                 transformed B-cell non-Hodgkin&#39;s lymphoma 
               
               
                 ipilimumab 
                 Bristol-Myers 
                 CTLA-4 
                 Metastatic melanoma 
               
               
                   
                 Squibb 
                   
                   
               
               
                 necitumumab 
                 Eli Lilly 
                 EGFR 
                 Metastatic squamous non-small cell lung 
               
               
                   
                   
                   
                 carcinoma 
               
               
                 nivolumab 
                 Bristol-Myers 
                 PD-1 
                 Metastatic melanoma 
               
               
                   
                 Squibb 
                   
                 Metastatic squamous non-small cell lung 
               
               
                   
                   
                   
                 carcinoma 
               
               
                 obinutuzumab 
                 Genentech 
                 CD20 
                 Chronic lymphocytic leukemia 
               
               
                 ofatumumab 
                 Glaxo Grp 
                 CD20 
                 Chronic lymphocytic leukemia 
               
               
                 olaratumab 
                 Eli Lilly 
                 PDGFRA 
                 Soft tissue sarcoma 
               
               
                 panitumumab 
                 Amgen 
                 EGFR 
                 Metastatic colorectal cancer 
               
               
                 pembrolizumab 
                 Merck 
                 PD-1 
                 Metastatic melanoma 
               
               
                 pertuzumab 
                 Genentech 
                 HER2 
                 Metastatic breast cancer 
               
               
                 ramucirumab 
                 Eli Lilly 
                 VEGFR2 
                 Gastric cancer 
               
               
                 rituximab 
                 Genentech 
                 CD20 
                 B-cell non-Hodgkin&#39;s lymphoma 
               
               
                 trastuzumab 
                 Genentech 
                 HER2 
                 Metastatic breast cancer 
               
               
                   
               
            
           
         
       
     
     Cancer-Specific Agents 
     In some embodiments, the therapeutic agents administered with the serotonin receptor inhibitors described herein are cancer-specific. Cancer-specific agents are agents that have been shown to be particularly effective against certain types of cancer. Cancer-specific agents that can be administered with the serotonin receptor inhibitors described herein are listed in Table 8 below. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 CANCER-SPECIFIC AGENTS 
               
            
           
           
               
               
            
               
                 Cancer type 
                 Agents 
               
               
                   
               
               
                 Pancreatic cancer 
                 Chemotherapeutics (Paclitaxel Albumin-stabilized Nanoparticle Formulation, 
               
               
                   
                 Erlotinib Hydrochloride, Everolimus, Fluorouracil Injection, Gemcitabine 
               
               
                   
                 Hydrochloride, Irinotecan Hydrochloride Liposome, Mitomycin C, Sunitinib 
               
               
                   
                 Malate, Folfirinox, Gemcitabine-Cisplatin, Gemcitabine-Oxaliplatin, Off, 
               
               
                   
                 Lanreotide Acetate, Abraxane, Gemcitabine, Irinotecan, 5-FU, Oxaliplatin) 
               
               
                 Melanoma 
                 Checkpoint inhibitors (pembro, ipi, nivolumab, durvalumab), BRaf inhibitors 
               
               
                   
                 (vemurafenib, debrafenib), MEK inhibitors, CDK4 inhibitors (ribociclib) 
               
               
                 Renal cell 
                 Checkpoint inhibitors (pembro, ipi, nivolumab, durvalumab), mTOR inhibitors 
               
               
                 carcinoma 
                 (everolimus), bevacizumab 
               
               
                 Lung cancer 
                 Checkpoint inhibitors (pembro, ipi, nivolumab, durvalumab), EGFR inhibitors 
               
               
                   
                 (erlotinib, gefitinib, cetuximab) 
               
               
                 Esophageal cancer 
                 Chemotherapeutic agents (5FU, docetaxel), trastuzumab 
               
               
                 Ovarian cancer 
                 Chemotherapeutics (taxanes, cisplatin) 
               
               
                 Uterine cancer 
                 Chemotherapeutics (taxanes, cisplatin) 
               
               
                 Head and Neck 
                 Checkpoint inhibitors (pembro, ipi, nivolumab, durvalumab), EGFR inhibitors 
               
               
                 cancer 
                 (erlotinib, gefitinib, cetuximab) 
               
               
                 Mesothelioma 
                 Chemotherapeutics (pemetrexed, cisplatin) 
               
               
                   
               
            
           
         
       
     
     Non-Drug Therapies 
     Another type of agent that can be administered in combination with a serotonin receptor inhibitor is a therapeutic agent that is a non-drug treatment. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia and/or surgical excision of tumor tissue. 
     CAR-T Therapy 
     Another therapy that can be employed in combination with the methods and compositions described herein is CAR-T therapy, or therapy with lymphocytes, such as autologous or allogeneic T cells, that have been modified to express a chimeric antigen receptor (CAR) that recognizes specific cancer antigens. Commonly, CARs contain a single chain fragment variable (scFv) region of an antibody or a binding domain specific for a tumor associated antigen (TAA) coupled via hinge and transmembrane regions to cytoplasmic domains of T cell signaling molecules. The most common lymphocyte activation moieties include a T cell costimulatory domain (e.g., CD28 and/or CD137) in tandem with a T cell effector function triggering (e.g. CD3) moiety. CARs have the ability to redirect T cell reactivity and specifity toward a selected target in a non-MHC restricted manner, exploiting the antigen-binding properties of monoclonal antibodies. The non-MHC restricted antigen recognition gives CAR-T cells the ability to bypass a major mechanism of tumor escape. 
     Neurotransmission Modulators 
     In some embodiments, the serotonin receptor inhibitor is administered in combination with a neurotransmission modulator (e.g., an agent that increases or decreases neurotransmission). A neurotransmission modulator can be used to modulate neural activity in a cancer or tumor that is innervated by nerves or to modulate immune cells that express neurotransmitter receptors. For example, in some embodiments, the neurotransmission modulator is a neurotransmitter or neurotransmitter receptor listed in Table 9 or 10, or an agonist or antagonist listed in Tables 11A-11J for a corresponding neurotransmitter pathway member. In some embodiments, the neurotransmission modulator is a neurotransmission modulator listed in Table 12. Neurotransmission modulators that increase neurotransmission include neurotransmitters and neurotransmitter receptors listed in Tables 9 and 10 and analogs thereof, and neurotransmitter agonists (e.g., small molecules that agonize a neurotransmitter receptor listed in Table 9). Exemplary agonists are listed in Tables 11A-11J. In some embodiments, neurotransmission is increased via administration, local delivery, or stabilization of neurotransmitters (e.g., ligands listed in Tables 9 or 10). Neurotransmission modulators that increase neurotransmission also include agents that increase neurotransmitter synthesis or release (e.g., agents that increase the activity of a biosynthetic protein encoded by a gene in Table 9 via stabilization, overexpression, or upregulation, or agents that increase the activity of a synaptic or vesicular protein via stabilization, overexpression, or upregulation), prevent neurotransmitter reuptake or degradation (e.g., agents that block or antagonize transporters that remove neurotransmitter from the synaptic cleft), increase neurotransmitter receptor activity (e.g., agents that increase the activity of a signaling protein encoded by a gene in Table 9 via stabilization, overexpression, agonism, or upregulation, or agents that upregulate, agonize, or stabilize a neurotransmitter receptor listed in Table 9), increase neurotransmitter receptor synthesis or membrane insertion, decrease neurotransmitter degradation, and regulate neurotransmitter receptor conformation (e.g., agents that bind to a receptor and keep it in an “open” or “primed” conformation). In some embodiments, the neurotransmitter receptor is a channel, the activity of which can be increased by agonizing, opening, stabilizing, or overexpressing the channel. Neurotransmission modulators can increase neurotransmission by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. Exemplary neurotransmission modulators are listed in Table 12. 
     Neurotransmission modulators that decrease neurotransmission include neurotransmitter antagonists (e.g., small molecules that antagonize a neurotransmitter receptor listed in Table 9). Exemplary antagonists are listed in Tables 11A-11J. Neurotransmission modulators that decrease neurotransmission also include agents that decrease neurotransmitter synthesis or release (e.g., agents that decrease the activity of a biosynthetic protein encoded by a gene in Table 9 via inhibition or downregulation, or agents that decrease the activity of a synaptic or vesicular protein via blocking, disrupting, downregulating, or antagonizing the protein), increase neurotransmitter reuptake or degradation (e.g., agents that agonize, open, or stabilize transporters that remove neurotransmitter from the synaptic cleft), decrease neurotransmitter receptor activity (e.g., agents that decrease the activity of a signaling protein encoded by a gene in Table 9 or via blocking or antagonizing the protein, or agents that block, antagonize, or downregulate a neurotransmitter receptor listed in Table 9), decrease neurotransmitter receptor synthesis or membrane insertion, increase neurotransmitter degradation, regulate neurotransmitter receptor conformation (e.g., agents that bind to a receptor and keep it in a “closed” or “inactive” conformation), and disrupt the pre- or postsynaptic machinery (e.g., agents that block or disrupt a structural protein, or agents that block, disrupt, downregulate, or antagonize a synaptic or vesicular protein). In some embodiments, the neurotransmitter receptor is a channel (e.g., a ligand or voltage gated ion channel), the activity of which can be decreased by blockade, antagonism, or inverse agonism of the channel. Neurotransmission modulators that decrease neurotransmission further include agents that sequester, block, antagonize, or degrade a neurotransmitter listed in Tables 9 or 10. Neurotransmission modulators that decrease or block neurotransmission include antibodies that bind to or block the function of neurotransmitters, neurotransmitter receptor antagonists, and toxins that disrupt synaptic release. Neurotransmission modulators can decrease neurotransmission by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. Neurotransmission modulator can be administered in any of the modalities described herein (e.g., antibody, small molecule, nucleic acid, polypeptide, or viral vector). 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 NEUROTRANSMITTER GENES &amp; PATHWAYS 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Accession 
                 Entrez 
               
               
                 Gene 
                 Pathway 
                 Type 
                 Number 
                 Gene ID 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 ABAT 
                 Neurotransmitter 
                 Biosynthesis 
                 P80404 
                 18 
               
               
                 ACHE 
                 Neurotransmitter 
                 Biosynthesis 
                 P22303 
                 43 
               
               
                 ADORA2A 
                 Neurotransmitter 
                 Receptor 
                 P29274 
                 135 
               
               
                 ADORA2B 
                 Neurotransmitter 
                 Receptor 
                 P29275 
                 136 
               
               
                 Adra1a 
                 Adrenergic/ 
                 Receptor 
                 P35348 
                 148 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Adra1b 
                 Adrenergic/ 
                 Receptor 
                 P35368 
                 147 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Adra1d 
                 Adrenergic/ 
                 Receptor 
                 P25100 
                 146 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Adra2a 
                 Adrenergic/ 
                 Receptor 
                 P08913 
                 150 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Adra2b 
                 Adrenergic/ 
                 Receptor 
                 P18089 
                 151 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Adra2c 
                 Adrenergic/ 
                 Receptor 
                 P18825 
                 152 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Adrb1 
                 Adrenergic/ 
                 Receptor 
                 P08588 
                 153 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Adrb2 
                 Adrenergic/ 
                 Receptor 
                 P07550 
                 154 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Adrb3 
                 Adrenergic/ 
                 Receptor 
                 P13945 
                 155 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Adrbk1 
                 Adrenergic 
                 Kinase 
                 P25098 
                 156 
               
               
                 Adrbk2 
                 Adrenergic 
                 Kinase 
                 P35626 
                 157 
               
               
                 BACE1 
                 Neurotransmitter 
                 Biosynthesis 
                 P56817 
                 23621 
               
               
                 BCHE 
                 Neurotransmitter 
                 Biosynthesis 
                 P06276 
                 590 
               
               
                 BRS3 
                 Neuromodulator 
                 Receptor 
                 P32247 
                 P32247 
               
               
                 C6orf89 
                 Neuromodulator 
                 Receptor 
                 Q6UWU4 
                 221477 
               
               
                 CHAT 
                 Neurotransmitter 
                 Biosynthesis 
                 P28329 
                 1103 
               
               
                 CHRFAM7A 
                 Neurotransmitter 
                 Receptor 
                 Q494W8 
                 89832 
               
               
                 Chrm1 
                 Cholinergic/ 
                 Receptor 
                 P11229 
                 1128 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrm2 
                 Cholinergic/ 
                 Receptor 
                 P08172 
                 1129 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrm3 
                 Cholinergic/ 
                 Receptor 
                 P20309 
                 1131 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrm4 
                 Cholinergic/ 
                 Receptor 
                 P08173 
                 1132 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrm5 
                 Cholinergic/ 
                 Receptor 
                 P08912 
                 1133 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrna1 
                 Cholinergic/ 
                 Receptor 
                 P02708 
                 1134 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrna10 
                 Cholinergic/ 
                 Receptor 
                 Q9GZZ6 
                 57053 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrna2 
                 Cholinergic/ 
                 Receptor 
                 Q15822 
                 1135 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrna3 
                 Cholinergic/ 
                 Receptor 
                 P32297 
                 1136 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrna4 
                 Cholinergic/ 
                 Receptor 
                 P43681 
                 1137 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrna5 
                 Cholinergic/ 
                 Receptor 
                 P30532 
                 1138 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrna6 
                 Cholinergic/ 
                 Receptor 
                 Q15825 
                 8973 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrna7 
                 Cholinergic/ 
                 Receptor 
                 P36544 
                 1139 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrna9 
                 Cholinergic/ 
                 Receptor 
                 Q9UGM1 
                 55584 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrnb1 
                 Cholinergic/ 
                 Receptor 
                 P11230 
                 1140 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrnb2 
                 Cholinergic/ 
                 Receptor 
                 P17787 
                 1141 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrnb3 
                 Cholinergic/ 
                 Receptor 
                 Q05901 
                 1142 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrnb4 
                 Cholinergic/ 
                 Receptor 
                 P30926 
                 1143 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrnd 
                 Cholinergic/ 
                 Receptor 
                 Q07001 
                 1144 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrne 
                 Cholinergic/ 
                 Receptor 
                 Q04844 
                 1145 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Chrng 
                 Cholinergic/ 
                 Receptor 
                 P07510 
                 1146 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 CNR1 
                 Cannabinoid/ 
                 Receptor 
                 P21554 
                 1268 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 CNR2 
                 Cannabinoid/ 
                 Receptor 
                 P34972 
                 1269 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 CNRIP1 
                 Neurotransmitter 
                 Receptor 
                 Q96F85 
                 25927 
               
               
                 COMT 
                 Neurotransmitter 
                 Biosynthesis 
                 P21964 
                 1312 
               
               
                 CPA4 
                 Neurotransmitter 
                 Biosynthesis 
                 Q9UI42 
                 51200 
               
               
                 CPE 
                 Neuropeptide/ 
                 Biosynthesis 
                 P16870 
                 1363 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 CREM 
                 Neurotransmitter 
                 Signaling 
                 Q03060 
                 1390 
               
               
                 DAGLA 
                 Neurotransmitter 
                 Biosynthesis 
                 Q9Y4D2 
                 747 
               
               
                   
                 (Cannabinoid) 
                   
                   
                   
               
               
                 DAGLB 
                 Neurotransmitter 
                 Biosynthesis 
                 Q8NCG7 
                 221955 
               
               
                   
                 (Cannabinoid) 
                   
                   
                   
               
               
                 DBH 
                 Neurotransmitter 
                 Biosynthesis 
                 P09172 
                 1621 
               
               
                 DDC 
                 Neurotransmitter 
                 Biosynthesis 
                 P20711 
                 1644 
               
               
                 DGKI 
                 Neurotransmitter 
                 Biosynthesis 
                 O75912 
                 9162 
               
               
                 DOPO 
                 Dopaminergic 
                 Receptor 
                 P09172 
                 1621 
               
               
                 DPP4 
                 Neurotransmitter 
                 Biosynthesis 
                 P27487 
                 1803 
               
               
                 Drd1 
                 Dopaminergic/ 
                 Receptor 
                 P21728 
                 1812 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Drd2 
                 Dopaminergic/ 
                 Receptor 
                 P14416 
                 1813 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Drd3 
                 Dopaminergic/ 
                 Receptor 
                 P35462 
                 1814 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Drd4 
                 Dopaminergic/ 
                 Receptor 
                 P21917 
                 1815 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 Drd5 
                 Dopaminergic/ 
                 Receptor 
                 P21918 
                 1816 
               
               
                   
                 Neurotransmitter 
                   
                   
                   
               
               
                 ECEL1 
                 Neurotransmitter 
                 Biosynthesis 
                 O95672 
                 9427 
               
               
                 FAAH 
                 Neurotransmitter 
                 Biosynthesis 
                 O00519 
                 2166 
               
               
                 FNTA 
                 Neurotransmitter 
                 Signaling 
                 P49354 
                 2339 
               
               
                 GABARAP 
                 Neurotransmitter 
                 Receptor 
                 O95166 
                 11337 
               
               
                 GABARAPL1 
                 Amine 
                 Receptor 
                 Q9H0R8 
                 23710 
               
               
                   
                 Neuromodulator 
                   
                   
                   
               
               
                 GABARAPL2 
                 Amine 
                 Receptor 
                 P60520 
                 11345 
               
               
                   
                 Neuromodulator 
                   
                   
                   
               
               
                 GABBR1 
                 Neurotransmitter 
                 Receptor 
                 Q9UBS5 
                 2550 
               
               
                 GABBR2 
                 Amine 
                 Receptor 
                 O75899 
                 9568 
               
               
                   
                 Neuromodulator 
                   
                   
                   
               
               
                 GABRA1 
                 Neurotransmitter 
                 Receptor 
                 P14867 
                 2554 
               
               
                 GABRA2 
                 Neurotransmitter 
                 Receptor 
                 P47869 
                 2555 
               
               
                 GABRA3 
                 Neurotransmitter 
                 Receptor 
                 P34903 
                 2556 
               
               
                 GABRA4 
                 Neurotransmitter 
                 Receptor 
                 P48169 
                 2557 
               
               
                 GABRA5 
                 Neurotransmitter 
                 Receptor 
                 P31644 
                 2558 
               
               
                 GABRA6 
                 Neurotransmitter 
                 Receptor 
                 Q16445 
                 2559 
               
               
                 GABRB1 
                 Neurotransmitter 
                 Receptor 
                 P18505 
                 2560 
               
               
                 GABRB2 
                 Neurotransmitter 
                 Receptor 
                 P47870 
                 2561 
               
               
                 GABRB3 
                 Neurotransmitter 
                 Receptor 
                 P28472 
                 2562 
               
               
                 GABRD 
                 Neurotransmitter 
                 Receptor 
                 O14764 
                 2563 
               
               
                 GABRE 
                 Neurotransmitter 
                 Receptor 
                 P78334 
                 2564 
               
               
                 GABRG1 
                 Neurotransmitter 
                 Receptor 
                 Q8N1C3 
                 2565 
               
               
                 GABRG2 
                 Neurotransmitter 
                 Receptor 
                 P18507 
                 2566 
               
               
                 GABRG3 
                 Neurotransmitter 
                 Receptor 
                 Q99928 
                 2567 
               
               
                 GABRP 
                 Neurotransmitter 
                 Receptor 
                 O00591 
                 2568 
               
               
                 GABRQ 
                 Neurotransmitter 
                 Receptor 
                 Q9UN88 
                 55879 
               
               
                 GABRR1 
                 Neurotransmitter 
                 Receptor 
                 P24046 
                 2569 
               
               
                 GABRR2 
                 Neurotransmitter 
                 Receptor 
                 P28476 
                 2570 
               
               
                 GABRR3 
                 Neurotransmitter 
                 Receptor 
                 A8MPY1 
                 200959 
               
               
                 GAD1 
                 Neurotransmitter 
                 Biosynthesis 
                 Q99259 
                 2571 
               
               
                 GAD2 
                 Neurotransmitter 
                 Biosynthesis 
                 Q05329 
                 2572 
               
               
                 GCHFR 
                 Neurotransmitter 
                 Biosynthesis 
                 P30047 
                 2644 
               
               
                 GLRA1 
                 Neurotransmitter 
                 Receptor 
                 P23415 
                 2741 
               
               
                 GLRA2 
                 Neurotransmitter 
                 Receptor 
                 P23416 
                 2742 
               
               
                 GLRA3 
                 Neurotransmitter 
                 Receptor 
                 O75311 
                 8001 
               
               
                 GLRA4 
                 Neurotransmitter 
                 Receptor 
                 Q5JXX5 
                 441509 
               
               
                 GLRB 
                 Neurotransmitter 
                 Receptor 
                 P48167 
                 2743 
               
               
                 GLS 
                 Neurotransmitter 
                 Biosynthesis 
                 O94925 
                 2744 
               
               
                 GLS2 
                 Neurotransmitter 
                 Biosynthesis 
                 Q9UI32 
                 27165 
               
               
                 GluA1 (GluR1) 
                 Amine 
                 Receptor 
                 P42261 
                 2890 
               
               
                   
                 Neuromodulator 
                   
                   
                   
               
               
                 GluK1 (GluR5) 
                 Amine 
                 Receptor 
                 P39086 
                 2897 
               
               
                   
                 Neuromodulator 
                   
                   
                   
               
               
                 GLUL 
                 Neurotransmitter 
                 Biosynthesis 
                 P15104 
                 2752 
               
               
                 GluN1(NR1) 
                 Amine 
                 Receptor 
                 Q05586 
                 2902 
               
               
                   
                 Neuromodulator 
                   
                   
                   
               
               
                 GNMT 
                 Neurotransmitter 
                 Biosynthesis 
                 Q14749 
                 27232 
               
               
                 GPER1 
                 Neurotransmitter 
                 Receptor 
                 Q99527 
                 2852 
               
               
                 GPR1 
                 Neurotransmitter 
                 Receptor 
                 P46091 
                 2825 
               
               
                 GPR139 
                 Neurotransmitter 
                 Receptor 
                 Q6DWJ6 
                 124274 
               
               
                 GPR143 
                 Neurotransmitter 
                 Receptor 
                 P51810 
                 4935 
               
               
                 GPR149 
                 Neurotransmitter 
                 Receptor 
                 Q86SP6 
                 344758 
               
               
                 GPR18 
                 Neurotransmitter 
                 Receptor 
                 Q14330 
                 2841 
               
               
                 GPR21 
                 Neurotransmitter 
                 Receptor 
                 Q99679 
                 2844 
               
               
                 GPR26 
                 Neurotransmitter 
                 Receptor 
                 Q8NDV2 
                 2849 
               
               
                 GPR3 
                 Neurotransmitter 
                 Receptor 
                 P46089 
                 2827 
               
               
                 GPR35 
                 Neurotransmitter 
                 Receptor 
                 Q9HC97 
                 2859 
               
               
                 GPR52 
                 Neurotransmitter 
                 Receptor 
                 Q9Y2T5 
                 9293 
               
               
                 GPR55 
                 Neurotransmitter 
                 Receptor 
                 Q9Y2T6 
                 9290 
               
               
                 GPR78 
                 Neurotransmitter 
                 Receptor 
                 Q96P69 
                 27201 
               
               
                 GPR83 
                 Neurotransmitter 
                 Receptor 
                 Q9NYM4 
                 10888 
               
               
                 GPR84 
                 Neurotransmitter 
                 Receptor 
                 Q9NQS5 
                 53831 
               
               
                 GPRASP1 
                 Neurotransmitter 
                 Receptor 
                 Q5JY77 
                 9737 
               
               
                 GPR50 
                 Amine 
                 Receptor 
                 Q13585 
                 9248 
               
               
                   
                 Neuromodulator 
                   
                   
                   
               
               
                 GRIA1 
                 Neurotransmitter 
                 Receptor 
                 P42261 
                 2890 
               
               
                 GRIA2 
                 Neurotransmitter 
                 Receptor 
                 P42262 
                 2891 
               
               
                 GRIA3 
                 Neurotransmitter 
                 Receptor 
                 P42263 
                 2892 
               
               
                 GRIA4 
                 Neurotransmitter 
                 Receptor 
                 P48058 
                 2893 
               
               
                 GRID1 
                 Neurotransmitter 
                 Receptor 
                 Q9ULK0 
                 2894 
               
               
                 GRID2 
                 Neurotransmitter 
                 Receptor 
                 O43424 
                 2895 
               
               
                 GRIK1 
                 Neurotransmitter 
                 Receptor 
                 P39086 
                 2897 
               
               
                 GRIK2 
                 Neurotransmitter 
                 Receptor 
                 Q13002 
                 2898 
               
               
                 GRIK3 
                 Neurotransmitter 
                 Receptor 
                 Q13003 
                 2899 
               
               
                 GRIK4 
                 Neurotransmitter 
                 Receptor 
                 Q16099 
                 2900 
               
               
                 GRIK5 
                 Neurotransmitter 
                 Receptor 
                 Q16478 
                 2901 
               
               
                 GRIN1 
                 Neurotransmitter 
                 Receptor 
                 Q05586 
                 2902 
               
               
                 GRIN2A 
                 Neurotransmitter 
                 Receptor 
                 Q12879 
                 2903 
               
               
                 GRIN2B 
                 Neurotransmitter 
                 Receptor 
                 Q13224 
                 2904 
               
               
                 GRIN2C 
                 Neurotransmitter 
                 Receptor 
                 Q14957 
                 2905 
               
               
                 GRIN2D 
                 Neurotransmitter 
                 Receptor 
                 O15399 
                 2906 
               
               
                 GRIN3A 
                 Neurotransmitter 
                 Receptor 
                 Q8TCU5 
                 116443 
               
               
                 GRIN3B 
                 Neurotransmitter 
                 Receptor 
                 O60391 
                 116444 
               
               
                 GRK2 
                 Neurotransmitter 
                 Receptor 
                 P25098 
                 156 
               
               
                 GRK3 
                 Neurotransmitter 
                 Receptor 
                 P35626 
                 157 
               
               
                 GRM1 
                 Neurotransmitter 
                 Receptor 
                 Q13255 
                 2911 
               
               
                 GRM2 
                 Neurotransmitter 
                 Receptor 
                 Q14416 
                 2912 
               
               
                 GRM3 
                 Neurotransmitter 
                 Receptor 
                 Q14832 
                 2913 
               
               
                 GRM4 
                 Neurotransmitter 
                 Receptor 
                 Q14833 
                 2914 
               
               
                 GRM5 
                 Neurotransmitter 
                 Receptor 
                 P41594 
                 2915 
               
               
                 GRM6 
                 Neurotransmitter 
                 Receptor 
                 O15303 
                 2916 
               
               
                 GRM7 
                 Neurotransmitter 
                 Receptor 
                 Q14831 
                 2917 
               
               
                 GRM8 
                 Neurotransmitter 
                 Receptor 
                 O00222 
                 2918 
               
               
                 HNMT 
                 Neurotransmitter 
                 Biosynthesis 
                 P50135 
                 3176 
               
               
                 HOMER1 
                 Neurotransmitter 
                 Receptor 
                 Q86YM7 
                 9456 
               
               
                 HRH1 
                 Neurotransmitter 
                 Receptor 
                 P35367 
                 3269 
               
               
                 HRH2 
                 Neurotransmitter 
                 Receptor 
                 P25021 
                 3274 
               
               
                 HRH3 
                 Neurotransmitter 
                 Receptor 
                 Q9Y5N1 
                 11255 
               
               
                 HRH4 
                 Neurotransmitter 
                 Receptor 
                 Q9H3N8 
                 59340 
               
               
                 ITPR1 
                 Neurotransmitter 
                 Signaling 
                 Q14643 
                 3708 
               
               
                 ITPR2 
                 Neurotransmitter 
                 Signaling 
                 Q14571 
                 3709 
               
               
                 ITPR3 
                 Neurotransmitter 
                 Signaling 
                 Q14573 
                 3710 
               
               
                 LYNX1 
                 Neurotransmitter 
                 Receptor 
                 Q9BZG9 
                 66004 
               
               
                 MAOA 
                 Neurotransmitter 
                 Biosynthesis 
                 P21397 
                 4128 
               
               
                 MAOB 
                 Neurotransmitter 
                 Biosynthesis 
                 P27338 
                 4129 
               
               
                 NAMPT 
                 Neurotransmitter 
                 Biosynthesis 
                 P43490 
                 10135 
               
               
                 NISCH 
                 Neurotransmitter 
                 Receptor 
                 Q9Y2I1 
                 11188 
               
               
                 NOS1 
                 Neurotransmitter 
                 Biosynthesis 
                 P29475 
                 4842 
               
               
                 NPTN 
                 Neurotransmitter 
                 Receptor 
                 Q9Y639 
                 27020 
               
               
                 P2RX1 
                 Neurotransmitter 
                 Receptor 
                 P51575 
                 5023 
               
               
                 P2RX2 
                 Neurotransmitter 
                 Receptor 
                 Q9UBL9 
                 22953 
               
               
                 P2RX3 
                 Neurotransmitter 
                 Receptor 
                 P56373 
                 5024 
               
               
                 P2RX4 
                 Neurotransmitter 
                 Receptor 
                 Q99571 
                 5025 
               
               
                 P2RX5 
                 Neurotransmitter 
                 Receptor 
                 Q93086 
                 5026 
               
               
                 P2RX6 
                 Neurotransmitter 
                 Receptor 
                 O15547 
                 9127 
               
               
                 P2RX7 
                 Neurotransmitter 
                 Receptor 
                 Q99572 
                 5027 
               
               
                 P2RY11 
                 Neurotransmitter 
                 Receptor 
                 q96G91 
                 5032 
               
               
                 PAH 
                 Neurotransmitter 
                 Biosynthesis 
                 P00439 
                 5053 
               
               
                 PC 
                 Neurotransmitter 
                 Biosynthesis 
                 P11498 
                 5091 
               
               
                 PDE1B 
                 Neurotransmitter 
                 Signaling 
                 Q01064 
                 5153 
               
               
                 PDE4A 
                 Neurotransmitter 
                 Signaling 
                 P27815 
                 5141 
               
               
                 PDE4D 
                 Neurotransmitter 
                 Signaling 
                 Q08499 
                 5144 
               
               
                 PHOX2A 
                 Neurotransmitter 
                 Biosynthesis 
                 O14813 
                 401 
               
               
                 PHOX2B 
                 Neurotransmitter 
                 Biosynthesis 
                 Q99453 
                 8929 
               
               
                 PIK3CA 
                 Neurotransmitter 
                 Signaling 
                 P42336 
                 5290 
               
               
                 PIK3CB 
                 Neurotransmitter 
                 Signaling 
                 P42338 
                 5291 
               
               
                 PIK3CG 
                 Neurotransmitter 
                 Signaling 
                 P48736 
                 5294 
               
               
                 PLCB1 
                 Neurotransmitter 
                 Signaling 
                 Q9N066 
                 23236 
               
               
                 PLCB2 
                 Neurotransmitter 
                 Signaling 
                 Q00722 
                 5330 
               
               
                 PLCB3 
                 Neurotransmitter 
                 Signaling 
                 Q01970 
                 5331 
               
               
                 PLCB4 
                 Neurotransmitter 
                 Signaling 
                 Q15147 
                 5332 
               
               
                 PLCD1 
                 Neurotransmitter 
                 Signaling 
                 P51178 
                 5333 
               
               
                 PLCEl 
                 Neurotransmitter 
                 Signaling 
                 Q9P212 
                 51196 
               
               
                 PLCG1 
                 Neurotransmitter 
                 Signaling 
                 P19174 
                 5335 
               
               
                 PLCL1 
                 Neurotransmitter 
                 Signaling 
                 Q15111 
                 5334 
               
               
                 PLCL2 
                 Neurotransmitter 
                 Signaling 
                 Q9UPR0 
                 23228 
               
               
                 PPP1CB 
                 Neurotransmitter 
                 Signaling 
                 P62140 
                 5500 
               
               
                 PPP1CC 
                 Neurotransmitter 
                 Signaling 
                 P36873 
                 5501 
               
               
                 PRIMA1 
                 Neurotransmitter 
                 Biosynthesis 
                 Q86XR5 
                 145270 
               
               
                 PRKACG 
                 Neurotransmitter 
                 Signaling 
                 P22612 
                 5568 
               
               
                 PRKAR2B 
                 Neurotransmitter 
                 Signaling 
                 P31323 
                 5577 
               
               
                 PRKCG 
                 Neurotransmitter 
                 Signaling 
                 P05129 
                 5582 
               
               
                 PRKX 
                 Neurotransmitter 
                 Signaling 
                 P51817 
                 5613 
               
               
                 RIC3 
                 Neurotransmitter 
                 Receptor 
                 Q7Z5B4 
                 79608 
               
               
                 SHANK3 
                 Neurotransmitter 
                 Signaling 
                 Q9BYB0 
                 85358 
               
               
                 SLC6A1 
                 Amine 
                 Transferase 
                 P30531 
                 6529 
               
               
                   
                 Neuromodulator 
                   
                   
                   
               
               
                 SLC6A13 
                 Amine 
                 Transferase 
                 Q9NSD5 
                 6540 
               
               
                   
                 Neuromodulator 
                   
                   
                   
               
               
                 Slc6a4 
                 Serotonin 
                 Transporter 
                 P31645 
                 6532 
               
               
                 SNX13 
                 Neurotransmitter 
                 Signaling 
                 Q9Y5W8 
                 23161 
               
               
                 TAAR1 
                 Amine 
                 Receptor 
                 Q96RJ0 
                 134864 
               
               
                   
                 Neuromodulator 
                   
                   
                   
               
               
                 TAAR2 
                 Amine 
                 Receptor 
                 Q9P1P5 
                 9287 
               
               
                   
                 Neuromodulator 
                   
                   
                   
               
               
                 TAAR5 
                 Neurotransmitter 
                 Receptor 
                 O14804 
                 9038 
               
               
                 TH 
                 Neurotransmitter 
                 Biosynthesis 
                 P07101 
                 7054 
               
               
                 TPH1 
                 Neurotransmitter 
                 Biosynthesis 
                 P17752 
                 7166 
               
               
                 TPH2 
                 Neurotransmitter 
                 Biosynthesis 
                 Q8IWU9 
                 121278 
               
               
                 TRHDE 
                 Neurotransmitter 
                 Biosynthesis 
                 Q9UKU6 
                 29953 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 NEUROTRANSMITTERS 
               
            
           
           
               
               
               
            
               
                 Ligand 
                 Pathway 
                 Type 
               
               
                   
               
               
                 2-Arachidonoylglycerol 
                 Endocannabinoid 
                 Ligand 
               
               
                 2-Arachidonyl glyceryl ether 
                 Endocannabinoid 
                 Ligand 
               
               
                 3-methoxytyramine 
                 Amines 
                 Ligand 
               
               
                 Acetylcholine 
                 Amino Acids 
                 Ligand 
               
               
                 Adenosine 
                 Purine 
                 Ligand 
               
               
                 Adenosine triphosphate 
                 Purine 
                 Ligand 
               
               
                 Agmatine 
                 Amino Acids 
                 Ligand 
               
               
                 Anandamide 
                 Endocannabinoid 
                 Ligand 
               
               
                 Aspartate 
                 Amino Acids 
                 Ligand 
               
               
                 Carbon monoxide 
                 Gas 
                 Ligand 
               
               
                 D-serine 
                 Amino Acids 
                 Ligand 
               
               
                 Dopamine 
                 Monoamines 
                 Ligand 
               
               
                 Dynorphin 
                 Opioids 
                 Ligand 
               
               
                 Endorphin 
                 Opioids 
                 Ligand 
               
               
                 Enkephalin 
                 Opioids 
                 Ligand 
               
               
                 Epinephrine 
                 Monoamines 
                 Ligand 
               
               
                 Gamma-aminobutyric acid 
                 Amino Acids 
                 Ligand 
               
               
                 Glutamate 
                 Amino Acids 
                 Ligand 
               
               
                 Glycine 
                 Amino Acids 
                 Ligand 
               
               
                 Histamine 
                 Monoamines 
                 Ligand 
               
               
                 N-Acetylaspartylglutamate 
                 Neuropeptides 
                 Ligand 
               
               
                 N-Arachidonoyl dopamine 
                 Endocannabinoid 
                 Ligand 
               
               
                 N-methylphenethylamine 
                 Amines 
                 Ligand 
               
               
                 N-methyltryptamine 
                 Amines 
                 Ligand 
               
               
                 Nitric oxide 
                 Gas 
                 Ligand 
               
               
                 Norepinephrine 
                 Monoamines 
                 Ligand 
               
               
                 Octopamine 
                 Amines 
                 Ligand 
               
               
                 Phenethylamine 
                 Amines 
                 Ligand 
               
               
                 Serotonin 
                 Monoamines 
                 Ligand 
               
               
                 Synephrine 
                 Amines 
                 Ligand 
               
               
                 Tryptamine 
                 Amines 
                 Ligand 
               
               
                 Tyramine 
                 Amines 
                 Ligand 
               
               
                 Virodhamine 
                 Endocannabinoid 
                 Ligand 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11A 
               
             
            
               
                   
               
               
                 AGONISTS AND ANTAGONIST AGENTS 
               
            
           
           
               
               
               
            
               
                 Gene 
                 Agonist 
                 Antagonist 
               
               
                   
               
               
                 Adrb2 
                 NCX 950 
                 Alprenolol 
               
               
                 Accession Number: 
                 Bitolterol 
                 Carvedilol 
               
               
                 P07550 
                 Isoetarine 
                 Desipramine 
               
               
                   
                 Norepinephrine 
                 Nadolol 
               
               
                   
                 Phenylpropanolamine 
                 Levobunolol 
               
               
                   
                 Dipivefrin 
                 Metipranolol 
               
               
                   
                 Epinephrine 
                 Bevantolol 
               
               
                   
                 Orciprenaline 
                 Oxprenolol 
               
               
                   
                 Dobutamine 
                 Nebivolol 
               
               
                   
                 Ritodrine 
                 Asenapine 
               
               
                   
                 Terbutaline 
                 Bupranolol 
               
               
                   
                 Salmeterol 
                 Penbutolol 
               
               
                   
                 Formoterol 
                 Celiprolol 
               
               
                   
                 Salbutamol 
                 Pindolol 
               
               
                   
                 Isoprenaline 
                 Acebutolol 
               
               
                   
                 Arbutamine 
                 Bopindolol 
               
               
                   
                 Arformoterol 
                   
               
               
                   
                 Fenoterol 
                   
               
               
                   
                 Pirbuterol 
                   
               
               
                   
                 Ephedra 
                   
               
               
                   
                 Procaterol 
                   
               
               
                   
                 Clenbuterol 
                   
               
               
                   
                 Bambuterol 
                   
               
               
                   
                 Indacaterol 
                   
               
               
                   
                 Droxidopa 
                   
               
               
                   
                 Olodaterol 
                   
               
               
                   
                 Vilanterol 
                   
               
               
                   
                 Pseudoephedrine 
                   
               
               
                   
                 Cabergoline 
                   
               
               
                   
                 Mirtazepine 
                   
               
               
                 Adra1d 
                 Midodrine 
                 Dapiprazole 
               
               
                 Accession Number: 
                 Norepinephrine 
                 Amitriptyline 
               
               
                 P25100 
                 Clonidine 
                 Alfuzosin 
               
               
                   
                 Oxymetazoline 
                 Promazine 
               
               
                   
                 Pergolide 
                 Prazosin 
               
               
                   
                 Bromocriptine 
                 Imipramine 
               
               
                   
                 Droxidopa 
                 Nortriptyline 
               
               
                   
                 Xylometazoline 
                 Doxazosin 
               
               
                   
                 Ergotamine 
                 Nicardipine 
               
               
                   
                 Cirazoline 
                 Dronedarone 
               
               
                   
                 Cabergoline 
                 Tamsulosin 
               
               
                   
                 Methoxamine 
                 Propiomazine 
               
               
                   
                 Epinephrine 
                 Phenoxybenzamine 
               
               
                   
                   
                 Carvedilol 
               
               
                   
                   
                 Doxepin 
               
               
                   
                   
                 Terazosin 
               
               
                   
                   
                 Quetiapine 
               
               
                   
                   
                 Methotrimeprazine 
               
               
                   
                   
                 Silodosin 
               
               
                 Adrb1 
                 Isoetarine 
                 Esmolol 
               
               
                 Accession Number: 
                 Norepinephrine 
                 Betaxolol 
               
               
                 P08588 
                 Phenylpropanolamine 
                 Metoprolol 
               
               
                   
                 Epinephrine 
                 Atenolol 
               
               
                   
                 Dobutamine 
                 Timolol 
               
               
                   
                 Salbutamol 
                 Sotalol 
               
               
                   
                 Isoprenaline 
                 Propranolol 
               
               
                   
                 Arbutamine 
                 Labetalol 
               
               
                   
                 Fenoterol 
                 Bisoprolol 
               
               
                   
                 Pirbuterol 
                 Alprenolol 
               
               
                   
                 Ephedra 
                 Amiodarone 
               
               
                   
                 Clenbuterol 
                 Carvedilol 
               
               
                   
                 Droxidopa 
                 Nadolol 
               
               
                   
                 Pseudoephedrine 
                 Levobunolol 
               
               
                   
                 Carteolol 
                 Metipranolol 
               
               
                   
                 Cabergoline 
                 Bevantolol 
               
               
                   
                 Mirtazapine 
                 Practolol 
               
               
                   
                 Loxapine 
                 Oxprenolol 
               
               
                   
                 Vortioxetine 
                 Celiprolol 
               
               
                   
                 Desipramine 
                 Nebivolol 
               
               
                   
                   
                 Asenapine 
               
               
                   
                   
                 Bupranolol 
               
               
                   
                   
                 Penbutolol 
               
               
                   
                   
                 Pindolol 
               
               
                   
                   
                 Acebutolol 
               
               
                   
                   
                 Bopindolol 
               
               
                   
                   
                 Cartelol 
               
               
                 Adrb3 
                 SR 58611 
                 Bopindolol 
               
               
                 Accession Number: 
                 Norepinephrine 
                 Propranolol 
               
               
                 P13945 
                 Epinephrine 
                 Bupranolol 
               
               
                   
                 Isoprenaline 
                   
               
               
                   
                 Arbutamine 
                   
               
               
                   
                 Fenoterol 
                   
               
               
                   
                 Ephedra 
                   
               
               
                   
                 Clenbuterol 
                   
               
               
                   
                 Droxidopa 
                   
               
               
                   
                 Mirabegron 
                   
               
               
                 Adrbk1 
                 ATP 
                 Alprenolol 
               
               
                 Accession Number: 
                 Carbachol 
                 Heparin 
               
               
                 P25098 
                 Dopamine 
                   
               
               
                   
                 Isoproterenol 
                   
               
               
                   
                 Morphine 
                   
               
               
                   
                 DAMGO 
                   
               
               
                   
                 histamine 
                   
               
               
                   
                 Acetylcholine 
                   
               
               
                   
                 Etorphine 
                   
               
               
                   
                 NMDA 
                   
               
               
                   
                 Dopamine 
                   
               
               
                 Adrbk2 
                 Isoproterenol 
                 Propranolol 
               
               
                 Accession Number: 
                 DAMGO 
                   
               
               
                 P26819 
                 ATP 
                   
               
               
                 Chrm3 
                 cgmp 
                 MT3 
               
               
                 Accession Number: 
                 ATP 
                 Hexocyclium 
               
               
                 P20309 
                 Cevimeline 
                 Himbacine 
               
               
                   
                 arecoline 
                 Biperiden 
               
               
                   
                 oxotremorine-M 
                 lithocholylcholine 
               
               
                   
                 NNC 11-1314 
                 AFDX384 
               
               
                   
                 xanomeline 
                 4-DAMP 
               
               
                   
                 oxotremorine 
                 hexahydrodifenidol 
               
               
                   
                 pentylthio-TZTP 
                 VU0255035 
               
               
                   
                 arecaidine propargyl ester 
                 N-methyl scopolamine 
               
               
                   
                 NNC 11-1607 
                 Darifenacin 
               
               
                   
                 furmethide 
                 Thiethylperazine 
               
               
                   
                 NNC 11-1585 
                 methoctramine 
               
               
                   
                 Acetylcholine 
                 silahexocyclium 
               
               
                   
                 methylfurmethide 
                 Strychnine 
               
               
                   
                 Bethanechol 
                 MT7 
               
               
                   
                 Carbachol 
                 Heparin 
               
               
                   
                 Succinylcholine 
                 Olanzapine 
               
               
                   
                 ALKS 27 
                 Pirenzepine 
               
               
                   
                 itopride 
                 Clidinium 
               
               
                   
                 methacholine 
                 Ipratropium 
               
               
                   
                 Meperidine 
                 Propantheline 
               
               
                   
                 Cinnarizine 
                 Dicyclomine 
               
               
                   
                 Trimipramine 
                 Darifenacin 
               
               
                   
                   
                 Tiotropium 
               
               
                   
                   
                 Atropine 
               
               
                   
                   
                 Scopolamine 
               
               
                   
                   
                 Amitriptyline 
               
               
                   
                   
                 Doxepin 
               
               
                   
                   
                 Lidocaine 
               
               
                   
                   
                 Nortriptyline 
               
               
                   
                   
                 Tropicamide 
               
               
                   
                   
                 Metixene 
               
               
                   
                   
                 Homatropine Methylbromide 
               
               
                   
                   
                 Solifenacin 
               
               
                   
                   
                 Glycopyrrolate 
               
               
                   
                   
                 Propiomazine 
               
               
                   
                   
                 Diphemanil Methylsulfate 
               
               
                   
                   
                 Promethazine 
               
               
                   
                   
                 Diphenidol 
               
               
                   
                   
                 Pancuroniurn 
               
               
                   
                   
                 Ziprasidone 
               
               
                   
                   
                 Quetiapine 
               
               
                   
                   
                 Imipramine 
               
               
                   
                   
                 Clozapine 
               
               
                   
                   
                 Cyproheptadine 
               
               
                   
                   
                 Aripiprazole 
               
               
                   
                   
                 Nicardipine 
               
               
                   
                   
                 Amoxapine 
               
               
                   
                   
                 Loxapine 
               
               
                   
                   
                 Promazine 
               
               
                   
                   
                 Oxyphencyclimine 
               
               
                   
                   
                 Anisotropine Methylbromide 
               
               
                   
                   
                 Tridihexethyl 
               
               
                   
                   
                 Chlorpromazine 
               
               
                   
                   
                 Ketamine 
               
               
                   
                   
                 Cyclosporin A 
               
               
                   
                   
                 Paroxetine 
               
               
                   
                   
                 Benzquinamide 
               
               
                   
                   
                 Tolterodine 
               
               
                   
                   
                 Oxybutynin 
               
               
                   
                   
                 Alcuronium 
               
               
                   
                   
                 WIN 62,577 
               
               
                   
                   
                 Tramadol 
               
               
                   
                   
                 Chlorprothixene 
               
               
                   
                   
                 Aclidiniurn 
               
               
                   
                   
                 Methotrimeprazine 
               
               
                   
                   
                 Umeclidinium 
               
               
                   
                   
                 Cryptenamine 
               
               
                   
                   
                 Mepenzolate 
               
               
                   
                   
                 Maprotiline 
               
               
                   
                   
                 Brompheniramine 
               
               
                   
                   
                 Isopropamide 
               
               
                   
                   
                 Trihexyphenidyl 
               
               
                   
                   
                 Ipratropium bromide 
               
               
                   
                   
                 Hyoscyamine 
               
               
                   
                   
                 Procyclidine 
               
               
                   
                   
                 Pipecuronium 
               
               
                   
                   
                 Fesoterodine 
               
               
                   
                   
                 Disopyramide 
               
               
                   
                   
                 Desipramine 
               
               
                   
                   
                 Mivacuriurn 
               
               
                 Chrna3 
                 Nicotine 
                 A-867744 
               
               
                 Accession Number: 
                 Varenicline 
                 NS1738 
               
               
                 P32297 
                 Acetylcholine 
                 Hexamethonium 
               
               
                   
                 Ethanol 
                 Mecamylamine 
               
               
                   
                 Cytisine 
                 Dextromethorphan 
               
               
                   
                 Levamisole 
                 Pentolinium 
               
               
                   
                 Galantamine 
                 Levomethadyl Acetate 
               
               
                   
                   
                 Bupropion 
               
               
                 Chrna6 
                 Nicotine 
                 Hexamethonium 
               
               
                 Accession Number: 
                 Cytisine 
                 Mecamylamine 
               
               
                 Q15825 
                 Varenicline 
                   
               
               
                   
                 Galantamine 
                   
               
               
                 Chrna9 
                 Nicotine 
                 Hexamethonium 
               
               
                 Accession Number: 
                 Galantamine 
                 Mecamylamine 
               
               
                 Q9UGM1 
                 Ethanol 
                 Tetraethylammonium 
               
               
                   
                   
                 Muscarine 
               
               
                   
                 ATG003 
                 Strychnine 
               
               
                   
                 Lobeline 
                   
               
               
                   
                 RPI-78M 
                   
               
               
                 Chrnb1 
                 Galantamine 
                   
               
               
                 Accession Number: 
                   
                   
               
               
                 P11230 
                   
                   
               
               
                 Chrnb4 
                 Nicotine 
                 Atropine 
               
               
                 Accession Number: 
                 Varenicline 
                 Oxybutynin 
               
               
                 P30926 
                 PNU-120596 
                 Pentolinium 
               
               
                   
                 Ethanol 
                 Dextromethorphan 
               
               
                   
                 Galantamine 
                   
               
               
                 Chrng 
                 Galantamine 
                   
               
               
                 Accession Number: 
                   
                   
               
               
                 P07510 
                   
                   
               
               
                 Adcyap1 
                 Nicotine 
                 Atropine 
               
               
                 Accession Number: 
                 CGMP 
                 PPADS 
               
               
                 P18509 
                 Apomorphine 
                 Onapristone 
               
               
                   
                 Suramin 
                 Muscarine 
               
               
                   
                 Nifedipine 
                 Haloperidol 
               
               
                   
                 ATP 
                 Astressin 
               
               
                   
                 Dihydrotestosterone 
                 Melatonin 
               
               
                   
                 Maxadilan 
                 Scopolamine 
               
               
                   
                 Dexamethasone 
                 Tetrodotoxin 
               
               
                   
                 Acetylcholine 
                 Apamin 
               
               
                   
                 Histamine 
                 Hexamethonium 
               
               
                   
                 Carbachol 
                 Indomethacin 
               
               
                   
                 NMDA 
                 Propranolol 
               
               
                   
                 Dopamine 
                 Bumetanide 
               
               
                   
                 Isoproterenol 
                 Progesterone 
               
               
                   
                 Salbutamol 
                 Charybdotoxin 
               
               
                   
                 Morphine 
                 Prazosin 
               
               
                   
                 Clonidine 
                   
               
               
                   
                 Nimodipine 
                   
               
               
                   
                 2,6-Diamino-Hexanoic Acid Amide 
                   
               
               
                 CYSLTR1 
                 Salbutamol 
                 Montelukast 
               
               
                 Accession Number: 
                 Dexamethasone 
                 Zafirlukast 
               
               
                 Q9Y271 
                 Arachidonic acid 
                 Cinalukast 
               
               
                   
                 Histamine 
                 Pranlukast 
               
               
                   
                   
                 Nedocromil 
               
               
                   
                   
                 Theophylline 
               
               
                   
                   
                 Indomethacin 
               
               
                   
                   
                 Zileuton 
               
               
                   
                   
                 Iralukast 
               
               
                   
                   
                 Pobilukast 
               
               
                   
                   
                 Sulukast 
               
               
                   
                   
                 Verlukast 
               
               
                 LTB4R 
                 LTB 
                 U75302 
               
               
                 Accession Number: 
                 ATP 
                 CP105696 
               
               
                 Q15722 
                 Dexamethasone 
                 CP-195543 
               
               
                   
                 cholesterol 
                 Etalocib 
               
               
                   
                 20-hydroxy-LTB&lt; 
                 SC-41930 
               
               
                   
                 12R-HETE 
                 LY255283 
               
               
                   
                 arachidonic acid 
                 Zafirlukast 
               
               
                   
                   
                 ONO-4057 
               
               
                   
                   
                 RO5101576 
               
               
                   
                   
                 BILL 260 
               
               
                 PENK 
                 Dopamine 
                 Naltrexone 
               
               
                 Accession Number: 
                 kainate 
                 Naloxone 
               
               
                 P01210 
                 NMDA 
                 Progesterone 
               
               
                   
                 DAMGO 
                   
               
               
                   
                 Morphine 
                   
               
               
                 Htr2c 
                 Apomorphine 
                 Melatonin 
               
               
                 Accession Number: 
                 Bifeprunox 
                 SB 224289 
               
               
                 P28335 
                 Tramadol 
                 LY334362 
               
               
                   
                 AL-37350A 
                 FR260010 
               
               
                   
                 5-MeO-DMT 
                 Sulpiride 
               
               
                   
                 BW723086 
                 Thiethylperazine 
               
               
                   
                 CGS-12066 
                 cyamemazine 
               
               
                   
                 DOI 
                 Mesulergine 
               
               
                   
                 5-CT 
                 SB 221284 
               
               
                   
                 YM348 
                 Zotepine 
               
               
                   
                 LSD 
                 Metergoline 
               
               
                   
                 xanomeline 
                 methiothepin 
               
               
                   
                 WAY-163909 
                 Spiperone 
               
               
                   
                 Dopamine 
                 SB 215505 
               
               
                   
                 LY344864 
                 Tiospirone 
               
               
                   
                 VER-3323 
                 SB 228357 
               
               
                   
                 TFMPP 
                 Pizotifen 
               
               
                   
                 8-OH-DPAT 
                 SB 206553 
               
               
                   
                 MK-212 
                 SB 204741 
               
               
                   
                 NMDA 
                 SDZ SER-082 
               
               
                   
                 org 12962 
                 Ritanserin 
               
               
                   
                 5-MeOT 
                 SB 242084 
               
               
                   
                 RU 24969 
                 S33084 
               
               
                   
                 Acetylcholine 
                 Roxindole 
               
               
                   
                 QUINPIROLE 
                 RS-127445 
               
               
                   
                 quipazine 
                 Terguride 
               
               
                   
                 tryptamine 
                 EGIS-7625 
               
               
                   
                 Ro 60-0175 
                 SB 243213 
               
               
                   
                 Oxymetazoline 
                 RS-102221 
               
               
                   
                 Ergotamine 
                 Olanzapine 
               
               
                   
                 Cabergoline 
                 Aripiprazole 
               
               
                   
                 Lorcaserin 
                 Agomelatine 
               
               
                   
                 Pergolide 
                 Ziprasidone 
               
               
                   
                 Methylergonovine 
                 Quetiapine 
               
               
                   
                 Renzapride 
                 Sarpogrelate 
               
               
                   
                 Pramipexole 
                 Perphenazine 
               
               
                   
                 GR-127935 
                 Thioridazine 
               
               
                   
                 BRL-15572 
                 Sertindole 
               
               
                   
                 ipsapirone 
                 Loxapine 
               
               
                   
                 SB 216641 
                 Methysergide 
               
               
                   
                 5L65.0155 
                 Risperidone 
               
               
                   
                 S 16924 
                 Asenapine 
               
               
                   
                 Bromocriptine 
                 Mianserin 
               
               
                   
                 Lisuride 
                 Clozapine 
               
               
                   
                 Tegaserod 
                 Trifluoperazine 
               
               
                   
                 Epicept NP-1 
                 Trazodone 
               
               
                   
                 dapoxetine 
                 Doxepin 
               
               
                   
                 Dexfenfluramine 
                 Nortriptyline 
               
               
                   
                 3,4- 
                 Chlorprothixene 
               
               
                   
                 Methylenedioxymethamphetamine 
                   
               
               
                   
                 Ropinirole 
                 Minaprine 
               
               
                   
                 Maprotiline 
                 Propiomazine 
               
               
                   
                 Desipramine 
                 Mirtazapine 
               
               
                   
                   
                 Amoxapine 
               
               
                   
                   
                 Yohimbine 
               
               
                   
                   
                 Cyproheptadine 
               
               
                   
                   
                 Imipramine 
               
               
                   
                   
                 Amitriptyline 
               
               
                   
                   
                 Promazine 
               
               
                   
                   
                 Chlorpromazine 
               
               
                   
                   
                 Ketamine 
               
               
                   
                   
                 Propranolol 
               
               
                   
                   
                 Fluoxetine 
               
               
                   
                   
                 Ketanserin 
               
               
                   
                   
                 Mesulergine 
               
               
                   
                   
                 AC-90179 
               
               
                   
                   
                 Ergoloid mesylate 2 
               
               
                   
                   
                 Methotrimeprazine 
               
               
                   
                   
                 Paliperidone 
               
               
                   
                   
                 Clomipramine 
               
               
                   
                   
                 Trimipramine 
               
               
                   
                   
                 Captodiame 
               
               
                   
                   
                 Nefazodone 
               
               
                 GABA Receptor 
                 Bamaluzole 
                 bicuculline 
               
               
                 Accession Numbers 
                 GABA 
                 Metrazol 
               
               
                 (Q9UBS5, O95166, 
                 Gabamide 
                 Flumazenil 
               
               
                 O75899, P28472, P18507, 
                 GABOB 
                 Thiothixine 
               
               
                 P47870, P47869, O14764) 
                 Gaboxadol 
                 Bupropion 
               
               
                   
                 Ibotenic acid 
                 Caffeine 
               
               
                   
                 Isoguvacine 
                   
               
               
                   
                 Isonipecotic acid 
                   
               
               
                   
                 Muscimol 
                   
               
               
                   
                 Phenibut 
                   
               
               
                   
                 Picamilon 
                   
               
               
                   
                 Progabide 
                   
               
               
                   
                 Quisqualamine 
                   
               
               
                   
                 SL 75102 
                   
               
               
                   
                 Thiomuscimol 
                   
               
               
                   
                 Alcohols (e.g., ethanol, isopropanol) 
                   
               
               
                   
                 Avermectins (e.g., ivermectin) 
                   
               
               
                   
                 Barbiturates (e.g., phenobarbital) 
                   
               
               
                   
                 Benzodiazepines 
                   
               
               
                   
                 Bromides (e.g., potassium bromide 
                   
               
               
                   
                 Carbamates (e.g., meprobamate, 
                   
               
               
                   
                 carisoprodol) 
                   
               
               
                   
                 Chloralose 
                   
               
               
                   
                 Chlormezanone 
                   
               
               
                   
                 Clomethiazole 
                   
               
               
                   
                 Dihydroergolines (e.g., ergoloid 
                   
               
               
                   
                 (dihydroergotoxine) 
                   
               
               
                   
                 Etazepine 
                   
               
               
                   
                 Etifoxine 
                   
               
               
                   
                 Imidazoles (e.g., etomidate) 
                   
               
               
                   
                 Kavalactones (found in kava) 
                   
               
               
                   
                 Loreclezole 
                   
               
               
                   
                 Neuroactive steroids (e.g., 
                   
               
               
                   
                 allopregnanolone, ganaxolone) 
                   
               
               
                   
                 Nonbenzodiazepines (e.g., 
                   
               
               
                   
                 zaleplon, zolpidem, zopiclone, 
                   
               
               
                   
                 eszopiclone) 
                   
               
               
                   
                 Petrichloral 
                   
               
               
                   
                 Phenols (e.g., propofol) 
                   
               
               
                   
                 Piperidinediones (e.g., glutethimide, 
                   
               
               
                   
                 methyprylon) 
                   
               
               
                   
                 Propanidid 
                   
               
               
                   
                 Pyrazolopyridines (e.g., etazolate) 
                   
               
               
                   
                 Quinazolinones (e.g., 
                   
               
               
                   
                 methaqualone) 
                   
               
               
                   
                 Skullcap constituents 
                   
               
               
                   
                 Stiripentol 
                   
               
               
                   
                 Sulfonylalkanes (e.g., 
                   
               
               
                   
                 sulfonmethane, tetronal, trional) 
                   
               
               
                   
                 Valerian constituents (e.g., valeric 
                   
               
               
                   
                 acid, valerenic acid) 
                   
               
               
                   
                 Volatiles/gases (e.g., chloral 
                   
               
               
                   
                 hydrate, chloroform, diethyl ether, 
                   
               
               
                   
                 sevoflurane) 
                   
               
               
                 Glutamate Receptor 
                 3,5-dihydroxyphenylglycine 
                 APICA 
               
               
                 Accession Number: 
                 eglumegad 
                 EGLU 
               
               
                 (P42261, P39086, 
                 Biphenylindanone A 
                 LY-341,495 
               
               
                 P39086, Q13585, P42261, 
                 DCG-IV 
                   
               
               
                 P42262, P42263, P48058, 
                 L-AP4 
                   
               
               
                 P39086, Q13002, 
                   
                   
               
               
                 Q13003, Q13003, 
                   
                   
               
               
                 Q16478, Q12879, 
                   
                   
               
               
                 Q14957, Q13224, 
                   
                   
               
               
                 Q14957, O15399, 
                   
                   
               
               
                 Q8TCU5, O60391) 
                   
                   
               
               
                 CNR1/CNR2 
                 N-Arachidonoylethanolamine 
                 SR 141716A 
               
               
                 Accession Number: 
                 2-Arachidonoyl-glycerol 
                 LY-320135 
               
               
                 (P21554, P34972) 
                 2-Arachidonoyl-glycerylether 
                 AM251 
               
               
                   
                 N-Arachidonoyl-dopamine 
                 AM281 
               
               
                   
                 0-Arachidonoyl-ethanolamine 
                 SR 144528 
               
               
                   
                 N-Arachidonoylethanolamine 
                 AM630 
               
               
                   
                 2-Arachidonoyl-glycerol 
                   
               
               
                   
                 2-Arachidonoyl-glycerylether 
                   
               
               
                   
                 N-Arachidonoyl-dopamine 
                   
               
               
                   
                 O-Arachidonoyl-ethanolamine 
                   
               
               
                   
                 Δ-9-THC 
                   
               
               
                   
                 CP-55,940 
                   
               
               
                   
                 R(+)-WIN 55,212-2 
                   
               
               
                   
                 HU-210 
                   
               
               
                   
                 Levonantradol 
                   
               
               
                   
                 Nabilone 
                   
               
               
                   
                 Methanandamide 
                   
               
               
                   
                 ACEA 
                   
               
               
                   
                 O-1812 
                   
               
               
                   
                 Δ9-THC 
                   
               
               
                   
                 CP-55,940 
                   
               
               
                   
                 R(+)-WIN 55,212-2 
                   
               
               
                   
                 HU-210 
                   
               
               
                   
                 Levonantradol 
                   
               
               
                   
                 Nabilone 
                   
               
               
                   
                 Methanandamide 
                   
               
               
                   
                 JWH-015 
                   
               
               
                   
                 JWH-133 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11B 
               
             
            
               
                   
               
               
                 ADRENERGIC AGONISTS AND ANTAGONISTS 
               
            
           
           
               
               
               
            
               
                 Receptor 
                 Agonist 
                 Antagonist 
               
               
                   
               
               
                 Non-selective 
                 adrenaline (epinephrine), 
                 carvedilol, arotinolol, and labetalol 
               
               
                   
                 noradrenaline (norepinephrine),  
                   
               
               
                   
                 isoprenaline (isoproterenol), 
                   
               
               
                   
                 dopamine, caffeine, nicotine, 
                   
               
               
                   
                 tyramine, methylphenidate, 
                   
               
               
                   
                 ephedrine and pseudophedrine. 
                   
               
               
                 α1 selective 
                 phenylephrine, methoxamine, 
                 acepromazine, alfuzosin, doxazosin, 
               
               
                 (ADRA1A, ADRA1B, 
                 midodrine, cirazoline, 
                 labetalol, phenoxybenzamine, 
               
               
                 ADRA1D) 
                 xylometazoline, metaraminol  
                 KW3902, phentolamine, prazosin, 
               
               
                   
                 chloroehtylclonidine,  
                 tamsulosin, terazosin, tolazoline, 
               
               
                   
                 oxymetazoline 
                 trazodone, amitriptyline, silodosin, 
               
               
                   
                   
                 clomipramine, doxepin, trimipramine, 
               
               
                   
                   
                 typical and atypical antipsychotics,  
               
               
                   
                   
                 and antihistamines, such as 
               
               
                   
                   
                 hyroxyzine 
               
               
                 α2 selective 
                 α-methyl dopa, clonidine, 
                 phentolamine, phenoxybenzamine, 
               
               
                 (ADRA2A, ADRA2B, 
                 brimonidine, agmatine, 
                 yohimbine, idazoxan, atipamezole, 
               
               
                 ADRA2C) 
                 dexmedetomidine, 
                 mirtazapine, tolazoline, trazodone, 
               
               
                   
                 medetomidine, romifidine 
                 and typical and atypical 
               
               
                   
                 chloroethylclonidine, 
                 antipsychotics 
               
               
                   
                 detomidine, lofexidine, xylazine, 
                   
               
               
                   
                 tizanidine, guanfacine, and amitraz 
                   
               
               
                 β1 selective  
                 Dobutamine 
                 metroprolol, atenolol, acebutolol,  
               
               
                 (ADRB1) 
                   
                 bisoprolol, betaxolol, levobetaxolol, 
               
               
                   
                   
                 esmolol, celiprolol, carteolol, 
               
               
                   
                   
                 landiolol, oxprenolol, propanolol, 
               
               
                   
                   
                 practolol, penbutolol, timolol, 
               
               
                   
                   
                 labetalol, nebivolol, levobunolol, 
               
               
                   
                   
                 nadolol, pindolol, sotalol, 
               
               
                   
                   
                 metipranolol, tertatolol, vortioxene 
               
               
                 β2 selective  
                 salbutamol, albuterol, bitolterol 
                 butaxamine, acebutolol, timolol, 
               
               
                 (ADRB2) 
                 mesylate, levabuterol, ritodrine, 
                 propanolol, levobunolol, carteolol, 
               
               
                   
                 metaproterenol, terbutaline, 
                 labetalol, pindolol, oxprenolol, 
               
               
                   
                 salmeterol, formoterol, and  
                 nadolol, metipranolol, penbutolol, 
               
               
                   
                 pirbuterol 
                 tertatolol, sotalol 
               
               
                 β3 selective  
                 L-796568, amibegron, solabegron, 
                 SR 59230A, arotinolol 
               
               
                 (ADRB3) 
                 mirabegron 
                   
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11C 
               
             
            
               
                   
               
               
                 DOPAMINE AGONISTS AND ANTAGONISTS 
               
            
           
           
               
               
               
            
               
                 Receptor 
                 Agonist 
                 Antagonist 
               
               
                   
               
               
                 Non-selective 
                 pramipexole, ropinirole, rotigotine,  
                 haloperidol, paliperidone, clozapine, 
               
               
                   
                 apomorphine,  
                 risperidone, olanzapine, quetiapine, 
               
               
                   
                 propylnorapomorphine, 
                 ziprasidone, metoclopramide, 
               
               
                   
                 bromocriptine, cabergoline, ciladopa, 
                 droperidol, domperidone, amoxapine, 
               
               
                   
                 dihydrexidine, dinapsoline, 
                 clomipramine, trimipramine, choline, 
               
               
                   
                 doxamthrine, epicriptine, lisuride,  
                 melatonin, acepromazine, 
               
               
                   
                 pergolide, piribedil, quinagolide, 
                 amisulpride, asenapine, azaperone, 
               
               
                   
                 roxindole, dopamine 
                 benperidol, bromopride, butaclamol, 
               
               
                   
                   
                 chlorpromazine, clebopride, 
               
               
                   
                   
                 chlorprothixene, clopenthixol, 
               
               
                   
                   
                 clocapramine, eticlopride, 
               
               
                   
                   
                 flupenthixol, fluphenazine, 
               
               
                   
                   
                 fluspirilene, hydroxyzine, itopride, 
               
               
                   
                   
                 iodobenzamide, levomepromazine, 
               
               
                   
                   
                 levosulpiride, loxapine, mesoridazine, 
               
               
                   
                   
                 metopimazine, mosapramine, 
               
               
                   
                   
                 nafadotride, nemonapride, penfluridol, 
               
               
                   
                   
                 perazine, perphenazine, pimozide, 
               
               
                   
                   
                 prochlorperazine, promazine, 
               
               
                   
                   
                 pipotiazine, raclopride, remoxipride, 
               
               
                   
                   
                 spiperone, spiroxatrine, stepholidine, 
               
               
                   
                   
                 sulpiride, sultopride, 
               
               
                   
                   
                 tetrahydropalmatine, thiethylperazine, 
               
               
                   
                   
                 thioridazine, thiothixene, tiapride, 
               
               
                   
                   
                 trifluoperazine, trifluperidol, 
               
               
                   
                   
                 triflupromazine, thioproperazine, 
               
               
                   
                   
                 taractan, zotepine, zuclopenthixol, 
               
               
                   
                   
                 ziprasidone, ANP-010, NGD-94-4 
               
               
                 D1 (DRD1) 
                 Fenoldopam, A-86929, 
                 SCH-23,390, SKF-83,959, Ecopipam, 
               
               
                   
                 dihydrexidine, dinapsoline, 
                 Clebopride, Flupenthixol, 
               
               
                   
                 dinoxyline, doxanthrine, SKF-81297,  
                 Zuclopenthixol, Taractan, PSYRX- 
               
               
                   
                 SKF-82958, SKF-38393, G-BR-APB,  
                 101, LuAF-35700, GLC-756, 
               
               
                   
                 dopexamine 
                 ADX10061, Zicronapine 
               
               
                 D2 (DRD2) 
                 Cabergoline, pergolide, quinelorane, 
                 Chloroethylnorapomorphine, 
               
               
                   
                 sumanirole, talipexole, piribedil, 
                 desmethoxyfallypride, domperidone,  
               
               
                   
                 quinpirole, quinelorane, dinoxyline,  
                 eticlopride, fallypride, hydroxyzine, 
               
               
                   
                 dopexamine 
                 itopride, L-741,626, SV 293, 
               
               
                   
                   
                 yohimbine, raclopride, sulpiride,  
               
               
                   
                   
                 paliperidone, penfluridol, quetiapine, 
               
               
                   
                   
                 lurasidone, risperidone, olanzapine,  
               
               
                   
                   
                 blonanserin, perphenazine,  
               
               
                   
                   
                 metoclopramide, trifluoperazine,  
               
               
                   
                   
                 clebopride, levosulpiride, flupenthixol, 
               
               
                   
                   
                 haloperidol, thioridazine, alizapride,  
               
               
                   
                   
                 amisulpride, asenapine, bromopride, 
               
               
                   
                   
                 bromperidol, clozapine, fluphenazine,  
               
               
                   
                   
                 perphanazine, loxapine,  
               
               
                   
                   
                 nemonapride, pericyazine,  
               
               
                   
                   
                 pipamperone, prochlorperazine, 
               
               
                   
                   
                 thioproperazine, thiethylperazine, 
               
               
                   
                   
                 tiapride, ziprasidone, zuclopenthixol,  
               
               
                   
                   
                 taractan, fluanisone, melperone,  
               
               
                   
                   
                 molindone, remoxipride, sultopride, 
               
               
                   
                   
                 ALKS 3831, APD-403, ONC201, 
               
               
                   
                   
                 pridopidine, DSP-1200, NG-101, 
               
               
                   
                   
                 TAK-906, ADN-1184, ADN-2013, AG-  
               
               
                   
                   
                 0098, DDD-016, IRL-626, KP303,  
               
               
                   
                   
                 ONC-206, PF-4363467, PGW-5, CG-  
               
               
                   
                   
                 209, ABT-925, AC90222, ACP-005, 
               
               
                   
                   
                 ADN-2157, CB030006, CLR-136, 
               
               
                   
                   
                 Egis-11150, Iloperidone, JNJ- 
               
               
                   
                   
                 37822681, DLP-115, AZ-001, S- 
               
               
                   
                   
                 33138, SLV-314, Y-931, YKP1358,  
               
               
                   
                   
                 YK-P1447, APD405, CP-903397, 
               
               
                   
                   
                 ocaperidone, zicronapine, TPN-902 
               
               
                 D3 (DRD3) 
                 Piribedil, quinpirole, captodiame,  
                 Domperidone, FAUC 365, 
               
               
                   
                 compound R, R-16, FAUC 54, FAUC  
                 nafadotride, raclopride,  
               
               
                   
                 73, PD-128,907, PF-219,061, PF- 
                 PNU-99,194, SB-277011-A, 
               
               
                   
                 592,379, CJ-1037, FAUC 460, FAUC 
                 sulpiride, risperidone, 
               
               
                   
                 346, cariprazine 
                 YQA14, U99194, SR 21502, 
               
               
                   
                   
                 levosulpiride, amisulpride, 
               
               
                   
                   
                 nemonapride, ziprasidone,  
               
               
                   
                   
                 taractan, sultopride, APD-403,  
               
               
                   
                   
                 F17464, ONC201, NG-101,  
               
               
                   
                   
                 TAK-906, ONC-206, PF-  
               
               
                   
                   
                 4363467,ABT-127, ABT-614,  
               
               
                   
                   
                 GSK-598809, GSK-618334,  
               
               
                   
                   
                 S-14297, S-33138, YKP1358,  
               
               
                   
                   
                 YK-P1447 
               
               
                 D4 (DRD4) 
                 WAY-100635, A-412,997, ABT-724,  
                 A-381393, FAUC 213, L-745,870, L- 
               
               
                   
                 ABT-670, FAUC 316, PD-168, 077, 
                 570,667, ML-398, fananserin, 
               
               
                   
                 CP-226,269 
                 clozapine, PNB-05, SPI-376, SPI- 
               
               
                   
                   
                 392, Lu-35-138, NGD-94-1 
               
               
                 D5 (DRD5) 
                 Dihydrexidine, rotigotine, SKF- 
                 SCH 23390 
               
               
                   
                 83,959, fenoldopam, 
                   
               
               
                 Partial 
                 aplindore, brexpiprazole, 
                   
               
               
                   
                 aripiprazole, CY-208,243, 
                   
               
               
                   
                 pardoprunox, phencyclidine, 
                   
               
               
                   
                 and salvinorin A 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11D 
               
             
            
               
                   
               
               
                 GABA AGONISTS AND ANTAGONISTS 
               
            
           
           
               
               
               
            
               
                 Receptor 
                 Agonist 
                 Antagonist 
               
               
                   
               
               
                 GABA A   
                 barbiturates (e.g., allobarbital, 
                 bicuculline, gabazine, hydrastine,  
               
               
                   
                 amobarbital, aprobarbital, alphenal, 
                 pitrazepin, sinomenine, tutin, 
               
               
                   
                 barbital, brallobarbital, 
                 thiocolchicoside, metrazol,  
               
               
                   
                 phenobarbital, secobarbital, 
                 securinine, gabazine 
               
               
                   
                 thiopental), bamaluzole, GABA, 
                   
               
               
                   
                 GABOB, gaboxadol, ibotenic acid, 
                   
               
               
                   
                 isoguvacine, isonipecotic acid, 
                   
               
               
                   
                 muscimol, phenibut, picamilon, 
                   
               
               
                   
                 progabide, quisqualamine, SL 
                   
               
               
                   
                 75102, thiomuscimol, positive 
                   
               
               
                   
                 allosteric modulators (PAMs) (e.g.,  
                   
               
               
                   
                 alcohols, such as ethanol and 
                   
               
               
                   
                 isopropanol; avermectins, such as 
                   
               
               
                   
                 ivermectin; benzodiazepines, such 
                   
               
               
                   
                 as diazepam, alprazolam, 
                   
               
               
                   
                 chlordiazepoxide, clonazepam, 
                   
               
               
                   
                 flunitrazepam, lorazepam, 
                   
               
               
                   
                 midazolam, oxazepam, prazepam, 
                   
               
               
                   
                 brotizolam, triazolam, estazolam, 
                   
               
               
                   
                 lormetazepam, nitrazepam, 
                   
               
               
                   
                 temazepam, flurazepam, 
                   
               
               
                   
                 clorazepate halazepam, prazepam, 
                   
               
               
                   
                 nimetazapem, adinazolam, and 
                   
               
               
                   
                 climazolam; bromides, such as 
                   
               
               
                   
                 potassium bromide; carbamates, 
                   
               
               
                   
                 such as meprobamate and 
                   
               
               
                   
                 carisoprodol; chloralose; 
                   
               
               
                   
                 chlormezanone; chlomethiazole; 
                   
               
               
                   
                 dihydroergolines, such as ergoloid; 
                   
               
               
                   
                 etazepine; etifoxine; imidazoles, 
                   
               
               
                   
                 such as etomidate; 
                   
               
               
                   
                 imidazopyridines, such as alpidem 
                   
               
               
                   
                 and necopdiem; kavalactones; 
                   
               
               
                   
                 loreclezole; neuroactive steroids, 
                   
               
               
                   
                 such as allogregnanolone, 
                   
               
               
                   
                 pregnanolone, 
                   
               
               
                   
                 dihydrodeoxycorticosterone, 
                   
               
               
                   
                 tetrahydrodeoxycortisosterone, 
                   
               
               
                   
                 androstenol, androsterone, 
                   
               
               
                   
                 etiocholanolone, 3α-androstanediol, 
                   
               
               
                   
                 5α, 5β, or 3α-dihydroprogesterone, 
                   
               
               
                   
                 and ganaxolone; 
                   
               
               
                   
                 nonbenzodiazepines, such as 
                   
               
               
                   
                 zalepon, zolpidem, zopiclone, and 
                   
               
               
                   
                 eszopiclone; petrichloral; phenols, 
                   
               
               
                   
                 such as propofol; piperidinediones, 
                   
               
               
                   
                 such as glutethimide and 
                   
               
               
                   
                 methyprylon; propanidid; 
                   
               
               
                   
                 pyrazolopyridines, such as 
                   
               
               
                   
                 etazolate; pyrazolopyrimidines, 
                   
               
               
                   
                 such as divaplon and fasiplon; 
                   
               
               
                   
                 cyclopyrrolones, sush as pagoclone 
                   
               
               
                   
                 and suproclone; β-cabolines, such 
                   
               
               
                   
                 as abecarnil and geodecarnil; 
                   
               
               
                   
                 quinazolinones, such as 
                   
               
               
                   
                 methaqualone;  Scutellaria   
                   
               
               
                   
                 constituents; stiripentol; 
                   
               
               
                   
                 sulfonylalkanes, such as 
                   
               
               
                   
                 sulfonomethane, teronal, and 
                   
               
               
                   
                 trional; Valerian constituents, such 
                   
               
               
                   
                 as valeric acid and valerenic acid; 
                   
               
               
                   
                 and gases, such as chloral hydrate, 
                   
               
               
                   
                 chloroform, homotaurine, diethyl 
                   
               
               
                   
                 ether, and sevoflurane. 
                   
               
               
                 GABA B   
                 1,4-butanediol, baclofen, GABA, 
                 CGP-35348, homotaurine, phaclofen, 
               
               
                   
                 Gabamide, GABOB, gamma- 
                 saclofen, and SCH-50911 
               
               
                   
                 butyrolactone, gamma- 
                   
               
               
                   
                 hydroxybutyric acid, gamma- 
                   
               
               
                   
                 hyrdoxyvaleric acid, gamma- 
                   
               
               
                   
                 valerolactone, isovaline, 
                   
               
               
                   
                 lesogaberan, phenibut, picamilon, 
                   
               
               
                   
                 progabide, homotaurine, SL-75102, 
                   
               
               
                   
                 tolgabide 
                   
               
               
                 GABA A -ρ 
                 CACA, CAMP, GABA, GABOB, N4-  
                 gabazine, gaboxadol, isonipecotic  
               
               
                   
                 chloroacetylcytosine arabinoside,  
                 acid, SKF-97,541, and (1,2,5,6- 
               
               
                   
                 picamilon, progabide, tolgabide,  
                 Tetrahydropyridin-4- 
               
               
                   
                 and neuroactive steroids, such as  
                 yl)methylphosphinic acid 
               
               
                   
                 allopregnanolone, THDOC, and  
                   
               
               
                   
                 alphaxolone 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11E 
               
             
            
               
                   
               
               
                 MUSCARINC AGONISTS AND ANTAGONISTS 
               
            
           
           
               
               
               
            
               
                 Receptor 
                 Agonist 
                 Antagonist 
               
               
                   
               
               
                 Chrm1 
                 AF102B, AF150(S), AF267B, 
                 atropine, dicycloverine, hyoscyamine,  
               
               
                   
                 acetylcholine, carbachol, 
                 ipratropium, mamba toxin muscarinic  
               
               
                   
                 cevimeline, muscarine, 
                 toxin 7 (MT7), olanzapine,  
               
               
                   
                 oxotremorine, pilocarpine, 
                 oxybutynin, pirenzepine, telenzepine,  
               
               
                   
                 vedaclidine, 77-LH-28-1, CDD- 
                 and tolterodine 
               
               
                   
                 0097, McN-A-343, L689,660, and  
                   
               
               
                   
                 xanomeline 
                   
               
               
                 Chrm2 
                 acetylcholine, methacholine, iper-8- 
                 atropine, dicycloverine, 
               
               
                   
                 naph, berbine, and 
                 hyoscyamine,otenzepad,  
               
               
                   
                 (2S,2′R,3′S,5′R)-1-methyl-2-(2- 
                 AQRA-741, AFDX-384, 
               
               
                   
                 methyl-1,3-oxathiolan-5- 
                 thorazine, diphenhydramine, 
               
               
                   
                 yl)pyrrolidine 3-sulfoxide methyl  
                 dimenhydrinate, ipratropium,  
               
               
                   
                 iodide 
                 oxybutynin, pirenzepine, 
               
               
                   
                   
                 methoctramine, tripitramine, 
               
               
                   
                   
                 gallamine, and tolterodine 
               
               
                 Chrm3 
                 acetylcholine, bethanechol, 
                 atropine, dicycloverine, hyoscyamine,  
               
               
                   
                 carbachol, L689, 660,  
                 alcidium bromide, 4-DAMP,  
               
               
                   
                 oxotremorine, pilocarpine,  
                 darifenacin, DAU-5884, HL-031,120,  
               
               
                   
                 aceclidine, arecoline, 
                 ipratropium, J-104,129, oxybutynin,  
               
               
                   
                 and cevimeline 
                 tiotropium, zamifenacin,  
               
               
                   
                   
                 and tolterodine 
               
               
                 Chrm4 
                 acetylcholine, carbachol, and 
                 AFDX-384, dicycloverine,  
               
               
                   
                 oxotremorine), and Chrm5 agonists  
                 himbacine, mamba toxin 3,  
               
               
                   
                 (e.g., acetylcholine, milameline,  
                 PD-102,807, PD-0298029,  
               
               
                   
                 sabcomeline 
                 and tropicamide 
               
               
                 Chrm5 
                 acetylcholine, milameline, 
                 VU-0488130, xanomeline 
               
               
                   
                 sabcomeline 
                   
               
               
                 Non-selective 
                   
                 scopolamine, hydroxyzine, 
               
               
                   
                   
                 doxylamine, dicyclomine, flavoxate,  
               
               
                   
                   
                 cyclopentolate, atropine methonitrate, 
               
               
                   
                   
                 trihexyphenidyl/benzhexol, 
               
               
                   
                   
                 solifenacin, benzatropine, 
               
               
                   
                   
                 mebeverine, and procyclidine 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11F 
               
             
            
               
                   
               
               
                 NICOTINIC AGONISTS AND ANTAGONISTS 
               
            
           
           
               
               
               
            
               
                 Receptor 
                 Agonist 
                 Antagonist 
               
               
                   
               
               
                 Chrna receptors 
                 choline, acetylcholine, carbachol,  
                 turbocurarine, bupropion, 
               
               
                   
                 methacholine, nicotine, varenicline  
                 mecamylamine, 18- 
               
               
                   
                 tartrate, galantamine hydrobromide, 
                 methozycoronaridine, 
               
               
                   
                 suxamethonium chloride 
                 hexamethonium, trimethaphan,  
               
               
                   
                 (succinylcholine chloride), 
                 atraciurium, doxacurium,  
               
               
                   
                 epibatidine, iobeline, 
                 mivacurium ,pancuronium, 
               
               
                   
                 decamethonium, isopronicline/TC- 
                 vecuronium, succinylcholine, 
               
               
                   
                 1734/AZD348 (TC-1734), AZD1446 
                 dextromethorphan, neramexane,  
               
               
                   
                 (TC-6683), TC-5619, TC-5214, MEM 
                 dextrophan, and 3-  
               
               
                   
                 3454 (RG3487), ABT-894, ABT-560,  
                 methoxymorphinan 
               
               
                   
                 EVP-6124, EVP-4473, PNU-282987,  
                   
               
               
                   
                 AR-R17779, SSR 189711, JN403,  
                   
               
               
                   
                 ABBF, PHA-543613, SEN12333,  
                   
               
               
                   
                 GTS-21/DMXB-A, AZD0328, A- 
                   
               
               
                   
                 582941, ABT-418, 5-iodo-A-85380, 
                   
               
               
                   
                 SIB-1765F, ABT-089, and ABT-594 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11G 
               
             
            
               
                   
               
               
                 GLUATAMATE RECEPTOR AGONISTS AND ANTAGONISTS 
               
            
           
           
               
               
               
            
               
                 Receptor 
                 Agonist 
                 Antagonist 
               
               
                   
               
               
                 Ionotropic (GRIA-14, 
                 AMPA, glutamic acid, ibotenic 
                 AP5, AP7, CPPene, selfotel, HU-211, 
               
               
                 GRIK1-5, and GRIN1- 
                 acid, kainic acid, NMDA,  
                 Huperzine A, gabapentin, 
               
               
                   
                 quisqualic 
                 remacemide, amantadine, 
               
               
                   
                   
                 atomoxetine, AZD6765, agmatine,  
               
               
                   
                   
                 chloroform, dextrallorphan, 
               
               
                   
                   
                 dextromethorphan, dextrorphan, 
               
               
                   
                   
                 diphenidine, dizocilpine (MK-801),  
               
               
                   
                   
                 ethanol, eticyclidine, gacyclidine, 
               
               
                   
                   
                 ibogaine, ifenprodil, ketamine,  
               
               
                   
                   
                 kynurenic acid, memantine, 
               
               
                   
                   
                 magnesium, methoxetamine, 
               
               
                   
                   
                 nitromemantine, nitrous oxide, PD- 
               
               
                   
                   
                 137889, perampanel, phencyclidine,  
               
               
                   
                   
                 rolicyclidine, tenocyclidine,  
               
               
                   
                   
                 methoxydine, tiletamine,  
               
               
                   
                   
                 neramexane, eliprodil, etoxadrol, 
               
               
                   
                   
                 dexoxadrol, WMS-2539, NEFA,  
               
               
                   
                   
                 delucemine, 8A-PDHQ, aptiganel,  
               
               
                   
                   
                 rhynchophylline 
               
               
                 Metabotropic (GRM1-8) 
                 L-AP4, ACPD, L-QA, CHPG, LY- 
                 AIDA, fenobam, MPEP, LY-367,385,  
               
               
                   
                 379,268, LY-354,740, ACPT, VU 
                 EGLU, CPPG, MAP4, MSOP, LY- 
               
               
                   
                 0155041 
                 341,495 
               
               
                 Glycine antagonists 
                   
                 rapastinel, NRX-1074, 7- 
               
               
                   
                   
                 chlorokynurenic acid, 4- 
               
               
                   
                   
                 chlorokynurenine, 5,7- 
               
               
                   
                   
                 dichlorokynurenic acid, kynurenic  
               
               
                   
                   
                 acid, TK-40, 1- 
               
               
                   
                   
                 aminocyclopropanecarboxylic acid 
               
               
                   
                   
                 (ACPC), L-phenylalanine, and xenon 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11H 
               
             
            
               
                   
               
               
                 HISTAMINE AGONISTS AND ANTAGONISTS 
               
            
           
           
               
               
               
            
               
                 Receptor 
                 Agonist 
                 Antagonist 
               
               
                   
               
               
                 Non-selective 
                 histamine dihydrochloride, HTMT  
                   
               
               
                   
                 dimaleate, 2-pyridylethlyamine 
                   
               
               
                   
                 dihydrochloride 
                   
               
               
                 H 1   
                   
                 acrivastine, azelastine, astemizole,  
               
               
                   
                   
                 bilastine, bromodiphenhydramine, 
               
               
                   
                   
                 brompheniramine, buclizine, 
               
               
                   
                   
                 carbinoxamine, cetirizine, cetirizine  
               
               
                   
                   
                 dihydrochloride, clemastine fumarate, 
               
               
                   
                   
                 clemizole hydrochloride, 
               
               
                   
                   
                 chlorodiphenhydramine, 
               
               
                   
                   
                 chlorphenamine, chlorpromazine, 
               
               
                   
                   
                 clemastine, cyclizine, cyproheptadine, 
               
               
                   
                   
                 dexbrompheniramine, 
               
               
                   
                   
                 dexchlorpheniramine, 
               
               
                   
                   
                 dimenhydrinate, dimethindene 
               
               
                   
                   
                 maleate, dimetindene, 
               
               
                   
                   
                 diphenhydramine, diphenhydramine 
               
               
                   
                   
                 hydrochloride, doxepin hydrochloride,  
               
               
                   
                   
                 doxylamine, ebastine, embramine, 
               
               
                   
                   
                 fexofenadine, fexofenadine 
               
               
                   
                   
                 hydrochloride, hydroxyzine, ketotifen  
               
               
                   
                   
                 fumarate, loratadine, meclizine, 
               
               
                   
                   
                 meclizine dihydrochloride, 
               
               
                   
                   
                 mepyramine maleate, mirtazapine,  
               
               
                   
                   
                 olopatadine, olopatadine  
               
               
                   
                   
                 hydrochloride, orphenadrine, 
               
               
                   
                   
                 phenindamine, pheniramine, 
               
               
                   
                   
                 phenyltoloxamine, promethazine,  
               
               
                   
                   
                 quetiapine, rupatadine, terfenadine, 
               
               
                   
                   
                 tripelennamine, zotepine, trans- 
               
               
                   
                   
                 triprolidine hydrochloride, and  
               
               
                   
                   
                 triprolidine 
               
               
                 H 1  inverse agonists 
                   
                 cetirizine, levocetirizine, 
               
               
                   
                   
                 desloratadine, and pyrilamine 
               
               
                 H 2   
                 betazole, impromidine, dimaprit  
                 aminopotentidine, cimetidine, 
               
               
                   
                 dihydrochloride, and amthamine 
                 famotidine, ICI 162,846, lafutidine,  
               
               
                   
                 dihyrdobromide 
                 nizatidine, ranitidine, ranitidine  
               
               
                   
                   
                 hyrdochloride, roxatidine, zolantadine 
               
               
                   
                   
                 dimaleate, and toitidine 
               
               
                 H 3   
                 imetit dihydropbromide, immepip  
                 clobenpropit, clobenpropit 
               
               
                   
                 dihyrdrobromide, immethridine 
                 dihydrobromide, A 3314440 
               
               
                   
                 dihydrobromide, α-Methylhistamine 
                 dihyrdochloride, BF 2649 
               
               
                   
                 dihydrobromide, N-methylhistamine 
                 hydrochloride, carcinine 
               
               
                   
                 dihydrochloride, proxyfan oxalate, 
                 ditrifluoroacetate, ABT-239, 
               
               
                   
                 and betahistine 
                 ciprofaxin, conessine, GT 2016, A- 
               
               
                   
                   
                 349,821, impentamine 
               
               
                   
                   
                 dihydrobromide, iodophenpropit 
               
               
                   
                   
                 dihydrobromide, JNJ 10181457 
               
               
                   
                   
                 dihydrochloride, JNJ 5207852 
               
               
                   
                   
                 dihydrochloride, ROS 234 dioxalate,  
               
               
                   
                   
                 SEN 12333, VUF 5681  
               
               
                   
                   
                 dihydrobromide, and thioperamide 
               
               
                 H 4   
                 imetit dihydropbromide, immepip 
                 thioperamide, JNJ 7777120, A 
               
               
                   
                 dihyrdrobromide, 4-methylhistamine 
                 943931 dihydrochloride, A 987306, 
               
               
                   
                 dihydrochloride, clobenpropit 
                 JNJ 10191584 maleate, and VUF- 
               
               
                   
                 dihydrobromide, VUF 10460, and 
                 6002 
               
               
                   
                 VUF 8430 dihydrobromide 
                   
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11I 
               
             
            
               
                   
               
               
                 CANNABINOID AGONISTS AND ANTAGONISTS 
               
            
           
           
               
               
               
            
               
                 Receptor 
                 Agonist 
                 Antagonist 
               
               
                   
               
               
                 Cannabinoid receptor  
                 Anandamide, N-Arachidonoyl 
                   
               
               
                 (non-selective) 
                 dopamine, 2-Arachidonoylglycerol 
                   
               
               
                   
                 (2-AG), 2-Arachidonyl glyceryl ether, 
                   
               
               
                   
                 Δ-9-Tetrahydrocannabinol, EGCG, 
                   
               
               
                   
                 Yangonin, AM-1221, AM-1235,AM-  
                   
               
               
                   
                 2232, UR-144, JWH-007, JWH-015,  
                   
               
               
                   
                 JWH-018, ACEA, ACPA, arvanil, CP 
                   
               
               
                   
                 47497, DEA, leelamine, 
                   
               
               
                   
                 methanandamide, NADA, noladin  
                   
               
               
                   
                 ether, oleamide, CB 65, GP-1a, GP- 
                   
               
               
                   
                 2a, GW 405833, HU 308, JWH-133, 
                   
               
               
                   
                 L-759,633, L-759,656, LEI 101, MDA 
                   
               
               
                   
                 19, and SER 601 
                   
               
               
                 CB 1    
                 ACEA, ACPA,  
                 rimonabant, cannabidiol, Δ 9 - 
               
               
                 receptor 
                 RVD-Hpα, (R)-(+)- 
                 tetrahydrocannabivarin (THCV),  
               
               
                   
                 methanandamide 
                 taranabant, otenabant, surinabant ,  
               
               
                   
                   
                 rosonabant, SLV-319, AVE1625, 
               
               
                   
                   
                 V24343, AM 251, AM 281, AM 6545,  
               
               
                   
                   
                 hemopressin, LY 320135, MJ 15, CP  
               
               
                   
                   
                 945598, NIDA 41020, PF 514273,  
               
               
                   
                   
                 SLV 319, SR1141716A, and TC- 
               
               
                   
                   
                 C14G 
               
               
                 CB 2    
                 CB 65, GP la, GP 2a, GW 405833,  
                 cannabidiol, Δ 9 - 
               
               
                 receptor 
                 HU 308, JWH 133, L-759,656, L- 
                 tetrahydrocannabivarin (THCV), AM  
               
               
                   
                 759,633, SER 601, LEI 101  
                 630, COR 170, JTE 907, and SR  
               
               
                   
                   
                 144528 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11J 
               
             
            
               
                   
               
               
                 PURINERGIC RECEPTOR AGONISTS AND ANTAGONISTS 
               
            
           
           
               
               
               
            
               
                 Receptor 
                 Agonist 
                 Antagonist 
               
               
                   
               
               
                 ADORA1 (P1 
                 Adenosine, N6- 
                 Caffeine, theophylline, 8-Cyclopentyl- 
               
               
                 adenosine receptor) 
                 Cyclopentyladenosine, N6-3- 
                 1,3-dimethylxanthine (CPX), 8- 
               
               
                   
                 methoxyl-4-hydroxybenzyl adenine  
                 Cyclopentyl-1, 3-dipropylxanthine 
               
               
                   
                 riboside (B2), CCPA, tecadenoson,  
                 (DPCPX), 8-Phenyl-1,3- 
               
               
                   
                 selodenoson, Certain 
                 dipropylxanthine, bamifylline, BG- 
               
               
                   
                 Benzodiazepines and Barbiturates, 
                 9719, BG09928, FK-453, FK838, 
               
               
                   
                 2′-MeCCPA, GR 79236, and SDZ 
                 rolofylline, N-0861, and PSB 36 
               
               
                   
                 WAG 994 
                   
               
               
                 ADORA2A (P1 
                 Adenosine, N6-3-methoxyl-4- 
                 Caffeine, theophylline, istradefylline, 
               
               
                 adenosine receptor) 
                 hydroxybenzyl adenine riboside  
                 SCH-58261, SCH-442,416, ATL-444,  
               
               
                   
                 (B2), YT-146, DPMA, UK-423,097,  
                 MSX-3, preladenant, SCH-412,348,  
               
               
                   
                 limonene, NECA, CV-3146, 
                 VER-6623, VER-6947, VER-7835,  
               
               
                   
                 binodenoson, ATL-146e, CGS- 
                 vipadenant, and ZM-241,385 
               
               
                   
                 21680, and Regadenoson 
                   
               
               
                 ADORA2B (P1 
                 Adenosine, 5′-N- 
                 Caffeine, theophylline, CVT-6883, 
               
               
                 adenosine receptor) 
                 ethylcarboxamidoadenosine, BAY  
                 ATL-801, compound 38, MRS-1706,  
               
               
                   
                 60-6583, LUF-5835, NECA, (S)- 
                 MRS-1754, OSIP-339,391, PSB-603, 
               
               
                   
                 PHPNECA, and LUF-5845 
                 PSB-0788, and PSB-1115 
               
               
                 ADORA3 (P1 
                 Adenosine, 2-(1-Hexynyl)-N- 
                 Caffeine, theophylline, MRS-1191, 
               
               
                 adenosine receptor) 
                 methyladenosine, CF-101 (IB- 
                 MRS-1220, MRS-1334, MRS- 
               
               
                   
                 MECA), CF-102, 2-C1-IB-MECA,  
                 1523, MRS-3777, MRE3008F20, 
               
               
                   
                 CP-532,903, inosine, LUF-6000, 
                 MRE3005F20, OT-7999, 
               
               
                   
                 and MRS-3558 
                 55R161421, KF-26777, PSB-10, 
               
               
                   
                   
                 PSB-11, and VUF-5574 
               
               
                 P2Y receptor 
                 ATP, ADP, UTP, UDP, UDP- 
                 clopidogrel, elinogrel, prasugrel, 
               
               
                   
                 glucose, 2-methylthioladenosine 5′  
                 ticlopidine, ticagrelor, AR-C 
               
               
                   
                 diphosphate (2-MeSADP), 
                 118925XX, AR-C 66096, AR-C 
               
               
                   
                 lysophosphatidic acid, PSB 1114,  
                 69931, AZD 1283, MRS 2179, MRS  
               
               
                   
                 PSB 0474, NF 546, MRS 2365,  
                 2211, MRS 2279, MRS 2500, MRS  
               
               
                   
                 MRS 2690, MRS 2693, MRS 2768,  
                 2578, NF 157, NF 340, PPADS, 
               
               
                   
                 MRS 2905, MRS 2957, MRS 4062,  
                 PPTN hydrochloride, PSD 0739, SAR 
               
               
                   
                 and denufosol (P2Y 2  agonist) 
                 216471, and suramin 
               
               
                 P2X receptor 
                 ATP 
                 A 438079, A 740003, A 804598, A  
               
               
                   
                   
                 839977, AZ 10606120, AZ 11645373, 
               
               
                   
                   
                 5-BDBD, BX 430, Evans Blue, JNJ 
               
               
                   
                   
                 47965567, KN-62, NF 023, NF 110, 
               
               
                   
                   
                 NF 157, NF 279, NF 449, PPADS, 
               
               
                   
                   
                 iso-PPADS, PPNDS, Ro 0437626, Ro  
               
               
                   
                   
                 51, RO-3, TC-P 262, suramin, TNP- 
               
               
                   
                   
                 ATP, and P2X7 antagonists NF279,  
               
               
                   
                   
                 calmidazolium, and KN-62 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 NEUROTRANSMISSION MODULATORS  
               
            
           
           
               
               
            
               
                 Type  
                 Modulators 
               
               
                   
               
               
                 Norepinephrine reuptake inhibitors 
                 amedalin, atomoxetine, CP-39,332, daledalin,  
               
               
                 (increase adrenergic neurotransmission)  
                 edivoxetine, esreboxetine, lortalamine, nisoxetine,  
               
               
                   
                 reboxetine, talopram, talsupram, tandamine,  
               
               
                   
                 viloxazine, bupropion, ciclazindol, manifaxine,  
               
               
                   
                 maprotiline, radafaxine, tapentadol, teniloxazine,  
               
               
                   
                 protriptyline, nortriptyline, and desipramine  
               
               
                 Norepineprhine-dopamine reuptake inhibitors  
                 amineptine, bupropion, desoxypipradrol,  
               
               
                 (increase adrenergic and dopamine  
                 dexmethylphenidate, difemetorex, diphenylprolinol,  
               
               
                 neurotransmission)  
                 ethylphenidate, fencamfamine, fencamine,  
               
               
                   
                 lefetamine, methylenedioxypyrovalerone,  
               
               
                   
                 methylphenidate, nomifensine, O-2172, oxolinic  
               
               
                   
                 acid, pipradrol, prolintane, pyrovalerone,  
               
               
                   
                 tametraline, and WY-46824  
               
               
                 Serotonin-norepinephrine-dopamine reuptake 
                 mazindol, nefazodone, sibutramine, venlafaxine,  
               
               
                 inhibitors (SNDRIs) and serotonin-norepinephrine 
                 esketamine, duloxetine, ketamine, phencyclidine,  
               
               
                 reuptake inhibitors (SNRIs)  
                 tripelennamine, mepiprazole, amitifadine, AN788,  
               
               
                 (increase adrengergic, dopamine, and serotonin  
                 ansofaxine, centanafadine, atomoxetine, 
               
               
                 neurotransmission)  
                 desvenlafaxine, milnacipran, levomilnacipran,  
               
               
                   
                 dasotraline, Lu AA34893, Lu AA37096, NS-2360,  
               
               
                   
                 tedatioxetine, tesofensine, bicifadine, BMS-  
               
               
                   
                 866,949, brasofensine, diclofensine, DOV-216,303,  
               
               
                   
                 EXP-561, liafensine, NS-2359, RG-7166, SEP-  
               
               
                   
                 227,162, SEP-228,425, SEP-228,432, naphyrone,  
               
               
                   
                 3,3-Diphenylcyclobutanamine, 3,4-  
               
               
                   
                 Dichlorotametraline, D-161, desmethylsertraline,  
               
               
                   
                 DMNPC, DOV-102,677, fezolamine,  
               
               
                   
                 GSK1360707F, indatraline, JNJ-7925476, JZ-IV-  
               
               
                   
                 10, JZAD-IV-22, LR-5182, methylnaphthidate, MI-4,  
               
               
                   
                 PRC200-SS, PRC050, PR0025, SKF-83,959, TP1,  
               
               
                   
                 phenyltropanes (e.g., WF-23, dichloropane, and  
               
               
                   
                 RTI-55),  Ginkgo biloba  extract, St John&#39;s Wort,  
               
               
                   
                 hyperforin, adhyperforin, and uliginosin B  
               
               
                 Dopamine reuptake inhibitors  
                 Dopamine reuptake inhbiitors (e.g., altropane,  
               
               
                 (increase dopamine neurotransmission)  
                 amfonelic acid, amineptine, BTCP, 3C-PEP, DBL-  
               
               
                   
                 583, difluoropine, GBR-12783, GBR-12935, GBR-  
               
               
                   
                 13069, GBR-13098, GYKI-52895, lometopane,  
               
               
                   
                 methylphenidate, ethylphenidate, modafinil,  
               
               
                   
                 armodafinil, RTI-229, vanoxerine, adrafinil,  
               
               
                   
                 benztropine, bupropion, fluorenol, medifoxamine,  
               
               
                   
                 metaphit, rimcazole, venlafaxine,  Chaenomeles   
               
               
                   
                   speciosa , and oroxylin A), dopamine releasing  
               
               
                   
                 agents (e.g., p-Tyramine), dextroamphetamine,  
               
               
                   
                 lisdexamfetamine, dexmethylphenidate, and  
               
               
                   
                 cathinone  
               
               
                 Dopamine prodrugs  
                 Levopoda, docarpamine 
               
               
                 (increase dopamine neurotransmission) 
                   
               
               
                 GABA reuptake inhibitors  
                 CL-996, deramciclane, gabaculine, guvacine,  
               
               
                 (increase GABA neurotransmission)  
                 nipecotic acid, NNC-711, NNC 05-2090, SKF-  
               
               
                   
                 89976A, SNAP-5114, tiagabine, and hyperforin  
               
               
                 GABA analogs  
                 gabapentin, butyric acid, valproic acid, valpromide,  
               
               
                 (increase GABA neurotransmission)  
                 valnoctamide, 3-hydroxybutanal, GHB, sodium,  
               
               
                   
                 oxybate, aceburic acid, GBL, GHBAL, GHV, GVL,  
               
               
                   
                 GHC, GCL, HOCPCA, UMB68, pregabalin, tolibut,  
               
               
                   
                 phaclofen, sacolfen, arecaidine, gaboxadol,  
               
               
                   
                 isonipecotic acid, 3-Methyl-GABA, AABA, BABA,  
               
               
                   
                 DAVA, GAVA, Glutamic acid, hopantenic acid,  
               
               
                   
                 piracetam, and vigabatrin  
               
               
                 GABA prodrugs  
                 L-Glutamine, N-Isonicotinoyl-GABA, picamilon,  
               
               
                 (increase GABA neurotransmission)  
                 progabide, tolgabide  
               
               
                 Acetylcholinesterase inhibitors  
                 carbamates, physostigmine, neostigmine,  
               
               
                 (increase nicotinic and muscarinic  
                 pyridostigmine, ambenonium, demecarium,  
               
               
                 neurotransmission)  
                 rivastigmine, phenanthrene derivatives,  
               
               
                   
                 galantamine, caffeine, rosmarinic acid, alpha-  
               
               
                   
                 pinene, piperidines, donepezil, tacrine,  
               
               
                   
                 edrophonium, Huperzine A, ladostigil, ungeremine,  
               
               
                   
                 lactucopicrin, dyflos, echothiophate, parathion, and  
               
               
                   
                 quasi-irreversible acetylcholinesterase inhibitors  
               
               
                 Serotonin reuptake inhibitors  
                 alaproclate, cericlamine, citalopram, dapoxetine,  
               
               
                 (increase serotonin neurotransmission)  
                 escitalopram, femoxetine, fluoxetine, fluvoxamine,  
               
               
                   
                 ifoxetine, indalpine, omiloxetine, panuramine,  
               
               
                   
                 paroxetine, pirandamine, RTI-353, sertraline,  
               
               
                   
                 zimelidine, desmethylcitalopram,  
               
               
                   
                 didesmethylcitalopram, seproxetine ((S)-  
               
               
                   
                 norfluoxetine), desvenlafaxine, cianopramine,  
               
               
                   
                 litoxetine, lubazodone, SB-649,915, trazodone,  
               
               
                   
                 vilazodone, vortioxetine, dextromethorphan,  
               
               
                   
                 dextropropoxyphene, dimenhydrinate,  
               
               
                   
                 diphenhydramine, mepyramine (pyrilamine),  
               
               
                   
                 mifepristone, delucemine, mesembrenone,  
               
               
                   
                 mesembrine, roxindole, duloxetine,  
               
               
                   
                 levomilnacipran, milnacipran, dapoxetine,  
               
               
                   
                 sibutramine, chlorpheniramine,  
               
               
                   
                 dextropmethorphan, and methadone  
               
               
                 Serotonin releasing agents  
                 chlorphentermine, cloforex, dexfenfluramine,  
               
               
                 (increase serotonin neurotransmission)  
                 etolorex, fenfluramine, flucetorex, indeloxazine,  
               
               
                   
                 levofenfluramine, tramadol, carbamazepine,  
               
               
                   
                 amiflamine (FLA-336), viqualine (PK-5078), 2-  
               
               
                   
                 Methyl-3,4-methylenedioxyamphetamine (2-Methyl-  
               
               
                   
                 MDA), 3-Methoxy-4-methylamphetamine (MMA), 3-  
               
               
                   
                 Methyl-4,5-methylenedioxyamphetamine (5-Methyl-  
               
               
                   
                 MDA), 3,4-Ethylenedioxy-N-methylamphetamine  
               
               
                   
                 (EDMA), 4-Methoxyamphetamine (PMA), 4-  
               
               
                   
                 Methoxy-N-ethylamphetamine (PMEA), 4-Methoxy-  
               
               
                   
                 N-methylamphetamine (PMMA), 4-  
               
               
                   
                 Methylthioamphetamine (4-MTA), 5-(2-  
               
               
                   
                 Aminopropyl)-2,3-dihydrobenzofuran (5-APDB), 5-  
               
               
                   
                 Indanyl-2-aminopropane (IAP), 5-Methoxy-6-  
               
               
                   
                 methylaminoindane (MMAI), 5-Trifluoromethyl-2-  
               
               
                   
                 aminoindane (TAI), 5,6-Methylenedioxy-2-  
               
               
                   
                 aminoindane (MDAI), 5,6-Methylenedioxy-N-  
               
               
                   
                 methyl-2-aminoindane (MDMAI), 6-Chloro-2-  
               
               
                   
                 aminotetralin (6-CAT), 6-Tetralinyl-2-aminopropane  
               
               
                   
                 (TAP), 6,7-Methylenedioxy-2-aminotetralin (MDAT),  
               
               
                   
                 6,7-Methylenedioxy-N-methyl-2-aminotetralin  
               
               
                   
                 (MDMAT), N-Ethyl-5-trifluoromethyl-2-aminoindane  
               
               
                   
                 (ETAI), N-Methyl-5-indanyl-2-aminopropane,  
               
               
                   
                 aminorex, MDMA, MDEA, MDA, MBDB, and  
               
               
                   
                 tryptamines, such as DMT, αMT, 5MeO-NMT,  
               
               
                   
                 NMT, NETP, Dimethyl-Serotonin, 5MeO-NET, αET  
               
               
                   
                 and αMT  
               
               
                 Excitatory amino acid reuptake inhibitors  
                 didydrokanic acid, WAY-213,613, L-trans-2,4-PDC,  
               
               
                 (increase Glutamate receptor neurotransmission) 
                 amphetamine, and L-Theanine  
               
               
                 Glycine reuptake inhibitors  
                 bitopertin, Org 24598, Org 25935, ALX-5407,  
               
               
                 (increase Glutamate receptor neurotransmission)  
                 sacrosine, Org 25543, and N-arachidonylglycerine  
               
               
                 Histidine decarboxylase inhibitors  
                 Tritoqualine, catechin  
               
               
                 (decrease histamine neurotransmission)  
                   
               
               
                 Endocannabinoid enhancers  
                 AM404, fatty acid amide hydrolase inhibitors (e.g.,  
               
               
                 (increase cannabinoid neurotransmission)  
                 AM374, ARN2508, BIA 10-2472, BMS-469908,  
               
               
                   
                 CAY-10402, JNJ-245, JNJ-1661010, JNJ-  
               
               
                   
                 28833155, JNJ-40413269, JNJ-42119779, JNJ-  
               
               
                   
                 42165279, MK-3168, MK-4409, MM-433593, OL-  
               
               
                   
                 92, OL-135, PF-622, PF-750, PF-3845, PF-  
               
               
                   
                 04457845, PF-04862853, RN-450, SA-47, SA-73,  
               
               
                   
                 SSR-411298, ST-4068, TK-25, URB524, URB597,  
               
               
                   
                 URB694, URB937, VER-156084, and V-158866  
               
               
                 Monoacylglycerol lipase inhibitors  
                 N-arachidonoyl maleimide, JZL184  
               
               
                 (increase cannabinoid neurotransmission)  
                   
               
               
                 Endocannabinoid transporter inhibitors  
                 SB-FI-26  
               
               
                 (increase cannabinoid neurotransmission)  
                   
               
               
                 Endocannabinoid reuptake inhibitors  
                 AM404, AM1172, LY-2183240, O-2093, OMDM-2,  
               
               
                 (increase cannabinoid neurotransmission) 
                 UCM-707, VDM-11, guineensine, ETI-T-24_B_I,  
               
               
                   
                 WOBE437, and RX-055  
               
               
                 Adenosine uptake inhibitors  
                 cilostazol, dilazep, and dipyramidole  
               
               
                 (increase purinergic neurotransmission) 
                   
               
               
                 Nucleoside transporter inhibitors  
                 8MDP, Decynium 22, 5-iodotubercidin, NBMPR,  
               
               
                 (increase purinergic neurotransmission)  
                 and TC-T 6000 
               
               
                   
               
            
           
         
       
     
     In some embodiments, the neurotransmission blocker is a neurotoxin listed in Table 13, or a functional fragment or variant thereof. Neurotoxins include, without limitation, convulsants, nerve agents, parasympathomimetics, and uranyl compounds. Neurotoxins may be bacterial in origin, or fungal in origin, or plant in origin, or derived from a venom or other natural product. Neurotoxins may be synthetic or engineered molecules, derived de novo or from a natural product. Suitable neurotoxins include but are not limited to botulinum toxin and conotoxin. Exemplary neurotoxins are listed in Table 13. 
     
       
         
           
               
             
               
                 TABLE 13 
               
               
                   
               
               
                 NEUROTOXINS  
               
               
                 NEUROTOXINS 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 2,4,5-Trihydroxyamphetamine  
                 Grayanotoxin  
               
               
                 2,4,5-Trihydroxymethamphetamine 
                 Hainantoxin  
               
               
                 3,4-Dichloroamphetamine  
                 Halcurin  
               
               
                 5,7-Dihydroxytryptamine 
                 Hefutoxin  
               
               
                 5-lodowillardiine  
                 Helothermine  
               
               
                 Ablomin  
                 Heteroscodratoxin-1  
               
               
                 Aconitine  
                 Histrionicotoxin  
               
               
                 Aconitum  
                 Homoquinolinic acid  
               
               
                 Aconitum anthora  
                 Hongotoxin  
               
               
                 AETX  
                 Huwentoxin  
               
               
                 Agelenin  
                 Ibotenic acid  
               
               
                 Agitoxin  
                 Ikitoxin  
               
               
                 Aldrin  
                 inhibitor cystine knot  
               
               
                 Alpha-Methyldopamine  
                 Jingzhaotoxin  
               
               
                 Alpha-neurotoxin  
                 Kainic acid  
               
               
                 Altitoxin  
                 Kaliseptine  
               
               
                 Anatoxin-a  
                 Kappa-bungarotoxin  
               
               
                 Androctonus australis hector insect toxin  
                 Kodaikanal mercury poisoning  
               
               
                 Anisatin  
                 Kurtoxin  
               
               
                 Anthopleurin  
                 Latrotoxin  
               
               
                 Antillatoxin  
                 Lq2  
               
               
                 Anuroctoxin  
                 Maitotoxin  
               
               
                 Apamin  
                 Margatoxin  
               
               
                 Arum italicum  
                 Maurotoxin  
               
               
                 Arum maculatum  
                 Mercury (element)  
               
               
                 Babycurus toxin 1  
                 Methanol  
               
               
                 Batrachotoxin  
                 Methiocarb  
               
               
                 BDS-1  
                 MPP+ 
               
               
                 Bestoxin  
                 MPTP  
               
               
                 Beta-Methylamino-L-alanine 
                 Nemertelline  
               
               
                 BgK  
                 Neosaxitoxin  
               
               
                 Birtoxin  
                 Nicotine  
               
               
                 BmKAEP  
                 N-Methylconiine  
               
               
                 BmTx3  
                 Oenanthotoxin  
               
               
                 BotIT2 
                 Oxalyldiaminopropionic acid  
               
               
                 BotIT6 
                 Oxidopamine  
               
               
                 Botulinum toxin  
                 Oxotoxin  
               
               
                 Brevetoxin  
                 Pahutoxin  
               
               
                 Bukatoxin  
                 Palytoxin  
               
               
                 Butantoxin  
                 Pandinotoxin  
               
               
                 Calcicludine 
                 Para-Bromoamphetamine  
               
               
                 Calciseptine  
                 Para-Chloroamphetamine  
               
               
                 Calitoxin  
                 Para-Chloromethamphetamine  
               
               
                 Caramboxin  
                 Para-Iodoamphetamine  
               
               
                 Carbon disulfide  
                 Penitrem A  
               
               
                 CgNa toxin  
                 Phaiodotoxin  
               
               
                 Charybdotoxin  
                 Phenol  
               
               
                 Cicutoxin  
                 Phoneutria nigriventer toxin-3  
               
               
                 Ciguatoxin  
                 Phrixotoxin  
               
               
                 Cll1 
                 Polyacrylamide  
               
               
                 Clostridium botulinum  
                 Poneratoxin  
               
               
                 Conantokins  
                 Psalmotoxin  
               
               
                 Conhydrine  
                 Pumiliotoxin  
               
               
                 Coniine  
                 Quinolinic acid  
               
               
                 Conotoxin  
                 Raventoxin  
               
               
                 Contryphan  
                 Resiniferatoxin  
               
               
                 Cssll  
                 Samandarin  
               
               
                 CSTX 
                 Saxitoxin  
               
               
                 Curare  
                 Scyllatoxin  
               
               
                 Cyanide poisoning  
                 Sea anemone neurotoxin  
               
               
                 Cylindrospermopsin  
                 Slotoxin  
               
               
                 Cypermethrin 
                 SNX-482  
               
               
                 Delta atracotoxin  
                 Stichodactyla toxin  
               
               
                 Dendrotoxin  
                 Taicatoxin  
               
               
                 Dieldrin  
                 Taipoxin  
               
               
                 Diisopropyl fluorophosphates  
                 Tamapin  
               
               
                 Dimethylmercury  
                 Tertiapin  
               
               
                 Discrepin  
                 Tetanospasmin  
               
               
                 Domoic acid  
                 Tetraethylammonium  
               
               
                 Dortoxin  
                 Tetramethylenedisulfotetramine  
               
               
                 DSP-4  
                 Tetrodotoxin  
               
               
                 Ergtoxin  
                 Tityustoxin  
               
               
                 Falcarinol 
                 Tricresyl phosphate  
               
               
                 Fenpropathrin  
                 TsIV  
               
               
                 Gabaculine  
                 Vanillotoxin  
               
               
                 Ginkgotoxin  
                 Veratridine  
               
               
                 Grammotoxin 
               
               
                   
               
            
           
         
       
     
     Antibodies 
     Neurotransmission modulators also include antibodies that bind to neurotransmitters or neurotransmitter receptors listed in Tables 9 and 10 and decrease neurotransmission. These antibodies include blocking and neutralizing antibodies. Antibodies to neurotransmitters or neurotransmitter receptors listed in Tables 9 and 10 can be generated by those of skill in the art using well established and routine methods. 
     Neuronal Growth Factor Modulators 
     In some embodiments, the serotonin receptor inhibitor is administered with a neuronal growth factor modulator (e.g., an agent that decreases or increases neurogenic/axonogenic signals, e.g., a neuronal growth factor or neuronal growth factor mimic, or an agonist or antagonist of a neuronal growth factor or neuronal growth factor receptor). For example, the neuronal growth factor modulator is a neuronal growth factor listed in Table 14, e.g., a neuronal growth factor having the sequence referenced by accession number or Entrez Gene ID in Table 14, or an analog thereof, e.g., a sequence having at least 75%, 80%, 85%, 90%, 90%, 98%, 99% identity to the sequence referenced by accession number or Entrez Gene ID in Table 14. Neuronal growth factor modulators also include agonists and antagonists of neuronal growth factors and neuronal growth factor receptors listed in Table 14. A neuronal growth factor modulator may increase or decrease neurogenesis, neuronal growth, neuronal differentiation, neurite outgrowth, synapse formation, synaptic maturation, synaptic refinement, or synaptic stabilization. Neuronal growth factor modulators regulate tissue innervation (e.g., innervation of a tumor) and the formation of synaptic connections between two or more neurons and between neurons and non-neural cells (e.g., between neurons and cancer cells). A neuronal growth factor modulator may block one or more of these processes (e.g., through the use of antibodies that block neuronal growth factors or their receptors) or promote one or more of these processes (e.g., through the use of neuronal growth factors or analogs thereof). Neuronal growth factor modulators can increase or decrease one of the above mentioned processes by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 200%, 500% or more. 
     In some embodiments, the neuronal growth factor modulator is one that increases neurogenic/axonogenic signals, e.g., the method includes administering to the subject or contacting a cell with a neuronal growth factor modulator in an amount and for a time sufficient to increase neurogenesis or axonogenesis. For example, the neuronal growth factor modulator that leads to an increase in neurogenesis or axonogenesis is a neurotrophic factor. Relevant neurotrophic factors include NGF, BDNF, ProNGF, Sortilin, TGFβ and TGFβ family ligands and receptors (e.g., TGFβR1, TGFβR2, TGFβ1, TGFβ2 TGFβ4), GFRα family ligands and receptors (e.g., GFRα1, GFRα2, GFRα3, GFRα4, GDNF), CNTF, LIF, neurturin, artemin, persephin, neurotrophin, chemokines, cytokines, and others listed in Table 14. Receptors for these factors may also be targeted, as well as downstream signaling pathways including Jak-Stat inducers, and cell cycle and MAPK signaling pathways. In some embodiments, the neuronal growth factor modulator increases neurogenesis, axonogenesis or any of the processes mentioned above by administering, locally delivering, or stabilizing a neuronal growth factor listed in Table 14, or by upregulating, agonizing, or stabilizing a neuronal growth factor receptor listed in Table 14. In some embodiments, the neuronal growth factor modulator increases neurogenesis, axonogenesis or any of the processes mentioned above by stabilizing, agonizing, overexpressing, or upregulating a signaling protein encoded by a gene that is downstream of a neuronal growth factor. In some embodiments, the neuronal growth factor modulator increases neurogenesis, axonogenesis or any of the processes mentioned above by stabilizing, overexpressing, or upregulating a synaptic or structural protein. Neurogenesis, axonogenesis, neuronal growth, neuronal differentiation, neurite outgrowth, synapse formation, synaptic maturation, synaptic refinement, or synaptic stabilization can be increased in the subject at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80% or more, compared to before the administration. Neurogenesis, axonogenesis, neuronal growth, neuronal differentiation, neurite outgrowth, synapse formation, synaptic maturation, synaptic refinement, or synaptic stabilization can be increased in the subject between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%. 
     In some embodiments, the neuronal growth factor modulator decreases neurogenic/axonogenic signals, e.g., the method includes administering to the subject or contacting a cell with a neuronal growth factor modulator in an amount and for a time sufficient to decrease neurogenesis, axonogenesis, or innervation. For example, the neuronal growth factor modulator that leads to a decrease in neurogenesis or axonogenesis is a blocking or neutralizing antibody against a neurotrophic factor. Relevant neurotrophic factors include NGF, BDNF, ProNGF, Sortilin, TGFβ and TGFβ family ligands and receptors (e.g., TGFβR1, TGFβR2, TGFβ1, TGFβ2 TGFβ4), GFRα family ligands and receptors (e.g., GFRα1, GFRα2, GFRα3, GFRα4, GDNF), CNTF, LIF, neurturin, artemin, persephin, neurotrophin, chemokines, cytokines, and others listed in Table 14. Receptors for these factors can also be targeted, as well as downstream signaling pathways including Jak-Stat inducers, and cell cycle and MAPK signaling pathways. In some embodiments, the neuronal growth factor modulator decreases neurogenesis, axonogenesis or any of the processes mentioned above by sequestering, blocking, antagonizing, degrading, or downregulating a neuronal growth factor or a neuronal growth factor receptor listed in Table 14. In some embodiments, the neuronal growth factor modulator decreases neurogenesis, axonogenesis or any of the processes mentioned above by blocking or antagonizing a signaling protein that is downstream of a neuronal growth factor. In some embodiments, the neuronal growth factor modulator decreases neurogenesis, axonogenesis or any of the processes mentioned above by blocking, disrupting, or antagonizing a synaptic or structural protein. Neurogenesis, axonogenesis, neuronal growth, neuronal differentiation, neurite outgrowth, synapse formation, synaptic maturation, synaptic refinement, synaptic stabilization, or tissue innervation can be decreased in the subject at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80% or more, compared to before the administration. 
     Neurogenesis, axonogenesis, neuronal growth, neuronal differentiation, neurite outgrowth, synapse formation, synaptic maturation, synaptic refinement, synaptic stabilization, or tissue innervation can be decreased in the subject between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%. Neuronal growth factor blockers can be administered in any of the modalities described herein (e.g., antibody, small molecule, nucleic acid, polypeptide, or viral vector). 
     In some embodiments, the neuronal growth factor modulator decreases the number of nerves in an affected tissue. For example, the subject has cancer (e.g., the subject has a highly innervated tumor). For example, the neuronal growth factor blocker is administered in an amount and for a time sufficient to decrease neurogenesis/axonogenesis. 
     Neuronal growth factor blockers include antibodies that bind to neuronal growth factors or neuronal growth factor receptors and decrease their signaling (e.g., blocking antibodies). Exemplary neuronal growth factor blocking antibodies are listed below in Table 15. Antibodies to neuronal growth factors listed in Table 14 can also be generated by those of skill in the art using well established and routine methods. 
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 NEURONAL GROWTH FACTORS  
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Accession  
                 Entrez  
               
               
                   
                 Gene  
                 Type  
                 Number 
                 Gene ID 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 ARTN  
                 Ligand  
                 Q5T4W7  
                 9048  
               
               
                   
                 BDNF  
                 Ligand  
                 P23560 
                 627  
               
               
                   
                 BDNF-AS  
                 Ligand 
                   
                 497258  
               
               
                   
                 BEX1  
                 Signaling  
                 Q9HBH7 
                 55859  
               
               
                   
                 BEX3  
                 Signaling  
                 Q00994  
                 27018  
               
               
                   
                 CD34  
                 Receptor  
                 P28906  
                 947  
               
               
                   
                 CDNF  
                 Ligand  
                 Q49AH0  
                 441549  
               
               
                   
                 CNTF  
                 Ligand  
                 P26441  
                 1270  
               
               
                   
                 CNTFR  
                 Receptor  
                 P26992  
                 1271  
               
               
                   
                 CRLF1  
                 Receptor 
                 O75462  
                 9244  
               
               
                   
                 CSPG5  
                 Ligand  
                 O95196  
                 10675  
               
               
                   
                 DCLK1  
                 Signaling  
                 O15075  
                 9201  
               
               
                   
                 DISC1  
                 Signaling 
                 Q9NRI5  
                 27185  
               
               
                   
                 DNAJC5 
                 Signaling 
                 Q9H3Z4  
                 80331  
               
               
                   
                 DPYSL2  
                 Signaling 
                 Q16555  
                 1808  
               
               
                   
                 DVL1  
                 Signaling 
                 O14640  
                 1855  
               
               
                   
                 EFNA5  
                 Ligand  
                 P52803  
                 1946  
               
               
                   
                 EGR3  
                 Signaling 
                 Q06889  
                 1960  
               
               
                   
                 ENO2  
                 Signaling 
                 P09104  
                 2026  
               
               
                   
                 EphA1  
                 Receptor 
                 P21709  
                 2041  
               
               
                   
                 EphA10 
                 Receptor 
                 Q5JZY3 
                 284656  
               
               
                   
                 EphA2  
                 Receptor  
                 P29317 
                 1969  
               
               
                   
                 EphA3  
                 Receptor 
                 P29320  
                 2042  
               
               
                   
                 EphA4  
                 Receptor 
                 P29317  
                 2043  
               
               
                   
                 EphA5  
                 Receptor  
                 P54756  
                 2044  
               
               
                   
                 EphA6  
                 Receptor  
                 Q9UF33  
                 285220  
               
               
                   
                 EphA7 
                 Receptor  
                 Q15375 
                 2045  
               
               
                   
                 EphA8 
                 Receptor  
                 P29322  
                 2046  
               
               
                   
                 EphB1  
                 Receptor 
                 P54762  
                 2047  
               
               
                   
                 EphB2 
                 Receptor  
                 P29323  
                 2048  
               
               
                   
                 EphB3  
                 Receptor  
                 P54753  
                 2049  
               
               
                   
                 EphB4  
                 Receptor  
                 P54760  
                 2050  
               
               
                   
                 EphB6  
                 Receptor  
                 O15197  
                 2051  
               
               
                   
                 ETBR2  
                 Receptor  
                 O60883 
                 9283  
               
               
                   
                 FSTL4  
                 Receptor  
                 Q6MZW2 
                 23105  
               
               
                   
                 GDNF 
                 Ligand  
                 P39905 
                 2668  
               
               
                   
                 GFRA1 
                 Receptor  
                 P56159 
                 2674  
               
               
                   
                 GFRA2 
                 Receptor  
                 O00451  
                 2675  
               
               
                   
                 GFRA3  
                 Receptor  
                 O60609  
                 2676  
               
               
                   
                 GFRA4 
                 Receptor  
                 Q9GZZ7  
                 64096  
               
               
                   
                 GPR37  
                 Receptor  
                 O15354  
                 2861  
               
               
                   
                 GPRIN1 
                 Signaling 
                 Q7Z2K8  
                 114787  
               
               
                   
                 GPRIN2  
                 Signaling 
                 O60269 
                 9721 
               
               
                   
                 GPRIN 
                 3 Signaling 
                 Q6ZVF9  
                 285513  
               
               
                   
                 GRB2 
                 Signaling  
                 P62993 
                 2885 
               
               
                   
                 GZF1  
                 Signaling 
                 Q9H116  
                 64412  
               
               
                   
                 IFNA1 
                 Ligand  
                 P01562 
                 3439  
               
               
                   
                 IGF1  
                 Ligand 
                 P05019  
                 3479 
               
               
                   
                 IGF2 
                 Ligand  
                 P01344  
                 3481  
               
               
                   
                 IL11RA 
                 Receptor  
                 Q14626  
                 3590  
               
               
                   
                 IL1B  
                 Ligand  
                 P01584  
                 3553 
               
               
                   
                 IL3  
                 Ligand  
                 P08700 3562  
                   
               
               
                   
                 IL4  
                 Ligand  
                 P05112 3565  
                   
               
               
                   
                 IL6  
                 Ligand  
                 P05231 3569  
                   
               
               
                   
                 IL6R  
                 Receptor  
                 P08887 3570  
                   
               
               
                   
                 IL6ST 
                 Signaling  
                 P40189 3572  
                   
               
               
                   
                 INS 
                 Ligand 
                 P01308 3630  
                   
               
               
                   
                 L1CAM 
                 Signaling  
                 P32004 3897  
                   
               
               
                   
                 LIF  
                 Ligand 
                 P15018 3976  
                   
               
               
                   
                 LIFR 
                 Receptor  
                 P42702 3977  
                   
               
               
                   
                 MAGED1 
                 Signaling 
                 Q9Y5V3 9500  
                   
               
               
                   
                 MANF  
                 Ligand  
                 P55145 7873  
                   
               
               
                   
                 NDNF  
                 Ligand  
                 Q8TB73 79625  
                   
               
               
                   
                 NENF  
                 Ligand  
                 Q9UMX5 29937  
                   
               
               
                   
                 NENFP1  
                 Ligand  
                   
                 106480294  
               
               
                   
                 NENFP2  
                 Ligand  
                   
                 100129880  
               
               
                   
                 NENFP3  
                 Ligand  
                   
                 106481703  
               
               
                   
                 NGF  
                 Ligand  
                 P01138  
                 4803  
               
               
                   
                 NGFR  
                 Receptor  
                 P08138 
                 4804  
               
               
                   
                 NRG1  
                 Ligand  
                 Q02297  
                 3084  
               
               
                   
                 NRP1  
                 Receptor 
                 O14786  
                 8829  
               
               
                   
                 NRTN  
                 Ligand 
                 Q99748  
                 902  
               
               
                   
                 NTF3  
                 Ligand  
                 P20783  
                 4908  
               
               
                   
                 NTF4  
                 Ligand  
                 P34130 
                 4909  
               
               
                   
                 NTRK1  
                 Receptor  
                 P04629  
                 4914  
               
               
                   
                 NTRK2  
                 Receptor  
                 Q16620  
                 4915  
               
               
                   
                 NTRK3  
                 Receptor  
                 Q16288  
                 4916  
               
               
                   
                 PDPK1  
                 Signaling  
                 O15530  
                 5170  
               
               
                   
                 PEDF 
                 Ligand  
                 P36955 
                 5176  
               
               
                   
                 PLEKHH3  
                 Signaling  
                 Q7Z736  
                 79990  
               
               
                   
                 PSAP  
                 Ligand  
                 P07602  
                 5660  
               
               
                   
                 PSEN1  
                 Signaling  
                 P49768 
                 5663  
               
               
                   
                 PSPN 
                 Ligand 
                 O70300  
                 5623  
               
               
                   
                 PTN  
                 Ligand  
                 P21246  
                 5764  
               
               
                   
                 RELN  
                 Ligand  
                 P78509  
                 5649  
               
               
                   
                 RET  
                 Signaling  
                 P07949  
                 5979  
               
               
                   
                 ROR1  
                 Receptor  
                 Q01973 
                 4919  
               
               
                   
                 ROR2 
                 Receptor  
                 Q01974  
                 4920  
               
               
                   
                 RPS6KA3  
                 Signaling  
                 P51812  
                 6197  
               
               
                   
                 SDC3  
                 Receptor  
                 O75056  
                 9672  
               
               
                   
                 SEMA3E 
                 Ligand  
                 O15041  
                 9723  
               
               
                   
                 SERPINE2 
                 Ligand  
                 P07093  
                 5270  
               
               
                   
                 SERPINF1  
                 Ligand  
                 P36955  
                 5176  
               
               
                   
                 SHC1  
                 Signaling  
                 P51812  
                 6464  
               
               
                   
                 SNTG1  
                 Biosynthesis 
                 P07602  
                 54212  
               
               
                   
                 S0RCS1  
                 Receptor  
                 O75056  
                 114815  
               
               
                   
                 SORCS2 
                 Receptor  
                 O15041  
                 57537  
               
               
                   
                 SORCS3 
                 Receptor  
                 P07093  
                 22986  
               
               
                   
                 SORT1  
                 Receptor  
                 Q99523  
                 6272  
               
               
                   
                 SULF1 
                 Signaling  
                 Q81WU6 
                 23213  
               
               
                   
                 SULF2 
                 Signaling  
                 Q8IWU5  
                 55959  
               
               
                   
                 TGFB1  
                 Ligand 
                 P01137  
                 7040  
               
               
                   
                 TGFB2  
                 Ligand  
                 P61812  
                 7042  
               
               
                   
                 TGFB3 
                 Ligand 
                 P10600  
                 7043  
               
               
                   
                 TMEM158 
                 Receptor  
                 Q8WZ71  
                 25907  
               
               
                   
                 TNF  
                 Ligand 
                 P01375  
                 7124  
               
               
                   
                 TPM3  
                 Receptor 
                 P06753 
                 7170  
               
               
                   
                 VEGFA 
                 Ligand  
                 P15692 
                 7422  
               
               
                   
                 VEGFB 
                 Ligand  
                 P49765  
                 7423  
               
               
                   
                 VGF 
                 Ligand 
                 O15240 
                 7425  
               
               
                   
                 XCR1  
                 Receptor  
                 P46094  
                 2829  
               
               
                   
                 ZN274  
                 Signaling  
                 Q96G06  
                 10782 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 NEURONAL GROWTH FACTOR ANTIBODIES  
               
            
           
           
               
               
               
            
               
                 Neuronal Growth Factor  
                 Antibody  
                 Company 
               
               
                   
               
               
                 BDNF  
                 3868 (agonist antibody)  
                 Pfizer 
               
               
                 BDNF 
                 29D7 (agonist antibody) 
                 Pfizer  
               
               
                 EphA3  
                 KB004  
                 KaloBios Pharmaceuticals, Inc.  
               
               
                 IFNA1  
                 Faralimomab  
                 Creative Biolabs  
               
               
                 IFNA1  
                 Sifalimumab (MEDI-545)  
                 MedImmune  
               
               
                 IFNA1  
                 Rontalizumab  
                 Genentech  
               
               
                 IGF  
                 Figitumumab (CP-751,871) - an 
                 Pfizer  
               
               
                   
                 IGR-1R MAb  
                   
               
               
                 IGF  
                 SCH717454 (Robatumamab,  
                 Merck  
               
               
                   
                 inhibits IGF initiated  
                   
               
               
                   
                 phosphorylation)  
                   
               
               
                 IGF 
                 Cixutumumab (IGF-1R antibody) 
                 Eli Lilly  
               
               
                 IGF  
                 Teprotumumab (IGF-1R  
                 Genmab/Roche  
               
               
                   
                 blocking antibody)  
                   
               
               
                 IGF-2  
                 Dusigitumab  
                 MedImmune/AstraZeneca  
               
               
                 IGF-2  
                 DX-2647  
                 Dyax/Shire  
               
               
                 IGF  
                 Xentuzumab  
                 Boehringer Ingelheim/Eli Lilly  
               
               
                 IGF  
                 Dalotuzumab (IGFR1 blocking  
                 Merck &amp; Co.  
               
               
                   
                 antibody)  
                   
               
               
                 IGF 
                 Figitumumab (IGFR1 blocking  
                 Pfizer  
               
               
                   
                 antibody)  
                   
               
               
                 IGF 
                 Ganitumab (IGFR1 blocking  
                 Amgen  
               
               
                   
                 antibody)  
                   
               
               
                 IGF  
                 Robatumumab (IGFR1 blocking  
                 Roche/Schering-Plough  
               
               
                   
                 antibody)  
                   
               
               
                 IL1B  
                 Canakinumab  
                 Novartis  
               
               
                 IL1B 
                 APX002  
                 Apexigen  
               
               
                 IL1B 
                 Gevokizumab  
                 XOMA  
               
               
                 IL4  
                 Pascolizumab 
                 GlaxoSmithKline  
               
               
                 IL4 
                 Dupilumab  
                 Regeneraon/Sanofi  
               
               
                 IL6  
                 Siltuximab  
                 Janssen Biotech, Inc.  
               
               
                 IL6  
                 Olokizumab  
                 UCB/R-Pharm  
               
               
                 IL6  
                 Elsilimomab  
                 Orphan Pharma International  
               
               
                 IL6  
                 Sirukumab  
                 Centocor  
               
               
                 IL6  
                 Clazakizumab  
                 Bristol Myers Squib/Alder  
               
               
                   
                   
                 Biopharmaceuticals  
               
               
                 IL6  
                 Gerilimzumab (ARGX-109) 
                 arGEN-X/RuiYi  
               
               
                 IL6  
                 FE301 
                 Ferring Pharmaceuticals  
               
               
                 IL6  
                 FM101 
                 Femta Pharmaceuticals  
               
               
                 IL-6R  
                 Sarilumab (directed against  
                 Regeneron/Sanofi  
               
               
                   
                 IL6R)  
                   
               
               
                 IL-6R  
                 Tocilizumab  
                 Hoffmann-La Roche/Chugai  
               
               
                 IL-6R 
                 Sapelizumab  
                 Chugai  
               
               
                 IL-6R  
                 Vobarilizumab  
                 Ablynx  
               
               
                 L1CAM  
                 AB417  
                 Creative biolabs  
               
               
                 L1CAM  
                 L1-9.3  
                 Creative biolabs  
               
               
                 L1CAM  
                 L1-14.10  
                 Biolegend  
               
               
                 NGF  
                 Tanezumab  
                 Pfizer  
               
               
                 NGF 
                 Fulranumab (JNJ-42160443),  
                 Amgen  
               
               
                 NGF  
                 MNAC13 (anti-TrkA, the NGF  
                 Creative Biolabs  
               
               
                   
                 receptor)  
                   
               
               
                 NGF  
                 mAb 911  
                 Rinat/Pfizer  
               
               
                 NGF  
                 Fasinumab  
                 Regeneron/Teva  
               
               
                 NRG1  
                 538.24  
                 Hoffman-La Roche  
               
               
                 NRP1  
                 Vesencumab  
                 Genentech/Roche  
               
               
                 ROR1  
                 Cirmtuzumab  
                 Oncternal Therapeutics  
               
               
                 SAP  
                 G5K2398852  
                 GlaxoSmithKline  
               
               
                 TGF6  
                 Fresolimumab (pan-TGFβ 
                 Genzyme/Aventis  
               
               
                   
                 antibody)  
                   
               
               
                 TGF6  
                 IMC-TR1 (LY3022859) (MAb  
                 Eli Lilly  
               
               
                   
                 against TGFβRII)  
                   
               
               
                 TGF6  
                 T6M1 (anti-TGFβ1 MAb)  
                 Eli Lilly  
               
               
                 TGF62 
                 Lerdelimumab (CAT-152)  
                 Genzyme  
               
               
                 TGF61  
                 Metelimumab  
                 Genzyme  
               
               
                 TGF61  
                 LY2382770  
                 Eli Lilly  
               
               
                 TGF6  
                 PF-03446962 (MAb against  
                 Pfizer  
               
               
                   
                 TGFβRI) 
                   
               
               
                 TNF  
                 Infliximab  
                 Janssen Biotech, Inc.  
               
               
                 TNF  
                 Adalimumab 
                 AbbVie Inc.  
               
               
                 TNF  
                 Certolizumab pegol  
                 UCB  
               
               
                 TNF 
                 Golimumab  
                 Janssen Biotech, Inc.  
               
               
                 TNF  
                 Afelimomab  
                   
               
               
                 TNF  
                 Placulumab  
                 Teva Pharmaceutical Industries,  
               
               
                   
                   
                 Inc.  
               
               
                 TNF  
                 Nerelimomab  
                 Chiron/Celltech  
               
               
                 TNF  
                 Ozoralizumab  
                 Pfizer/Ablynx  
               
               
                 VEGFA  
                 Bevacizumab  
                 Genentech  
               
               
                 VEGFA  
                 Ranibizumab  
                 Genentech  
               
               
                 VEGF  
                 Alacizumab pegol (anti-  
                 UCB  
               
               
                   
                 VEGFR2)  
                   
               
               
                 VEGFA  
                 Brolucizumab  
                 Novartis 
               
               
                 VEGF 
                 Icrucumab (anti-VEGFR1) 
                 Eli Lilly 
               
               
                 VEGF  
                 Ramucirumab (anti-VEGFR2)  
                 Eli Lilly 
               
               
                   
               
            
           
         
       
     
     Neuronal growth factor modulators also include agents that agonize or antagonize neuronal growth factors and neuronal growth factor receptors. For example, neuronal growth factor modulators include TNF inhibitors (e.g., etanercept, thalidomide, lenalidomide, pomalidomide, pentoxifylline, bupropion, and DOI), TGFβ1 inhibitors, (e.g., disitertide (P144)), TGFβ2 inhibitors (e.g., trabedersen (AP12009)). Exemplary neuronal growth factor agonists and antagonists are listed in Table 15. 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 NEURONAL GROWTH FACTOR AGONISTS AND ANTAGONISTS  
               
            
           
           
               
               
               
            
               
                 Growth Factor  
                 Agonist  
                 Antagonist 
               
               
                   
               
               
                 TrkA  
                 NGF, amitriptyline, and  
                 ALE-0540  
               
               
                   
                 gambogic amide, gambogic acid  
                   
               
               
                 TrkB  
                 BDNF, NT3, NT4, 3,7-  
                 ANA-12, cyclotraxin B, and  
               
               
                   
                 Dihydroxyflavone, 3,7,8,2′-  
                 gossypetin  
               
               
                   
                 Tetrahydroxyflavone, 4′-  
                   
               
               
                   
                 Dimethylamino-7,8-  
                   
               
               
                   
                 dihydroxyflavone, 7,3′-  
                   
               
               
                   
                 Dihydroxyflavone, 7,8-  
                   
               
               
                   
                 Dihydroxyflavone, 7,8,2′-  
                   
               
               
                   
                 Trihydroxyflavone, 7,8,3′-  
                   
               
               
                   
                 Trihydroxyflavone, Amitriptyline,  
                   
               
               
                   
                 Deoxygedunin, Diosmetin,  
                   
               
               
                   
                 HIOC, LM22A-4, N-  
                   
               
               
                   
                 Acetylserotonin, Norwogonin  
                   
               
               
                   
                 (5,7,8-THF), R7, LM22A4, and  
                   
               
               
                   
                 TDP6  
                   
               
               
                 Pan-Trk receptor  
                   
                 entrectinib (RXDX-101), AG  
               
               
                   
                   
                 879, GNF 5837, GW 441756,  
               
               
                   
                   
                 and PF 06273340  
               
               
                 GFRα1R  
                 GDNF and XIB4035  
                   
               
               
                 VEGF receptor  
                   
                 AEE 788, AG 879, AP 24534,  
               
               
                   
                   
                 axitinib, DMH4, GSK 1363089,  
               
               
                   
                   
                 Ki 8751, RAF 265, SU 4312, SU  
               
               
                   
                   
                 5402, SU 5416, SU 6668,  
               
               
                   
                   
                 sunitinib, toceranib, vatalanib,  
               
               
                   
                   
                 XL 184, ZM 306416, and ZM  
               
               
                   
                   
                 323881  
               
               
                 TGFβRI 
                   
                 galunisertib (LY2157299), TEW-  
               
               
                   
                   
                 7197, SB-431542, A 83-01, D  
               
               
                   
                   
                 4476, GW 788388, LY 364947,  
               
               
                   
                   
                 R 268712, RepSox, SB 505124,  
               
               
                   
                   
                 SB 525334, and SD 208 
               
               
                   
               
            
           
         
       
     
     In any of the combination therapy approaches described herein, the first and second therapeutic agent (e.g., a serotonin receptor inhibitor described herein and the additional therapeutic agent) are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after the second therapeutic agent. 
     Diagnosis and Prognosis of Serotonin Receptor-Associated Cancer 
     The methods described herein include methods of diagnosing or identifying patients with serotonin receptor-associated cancer. Subjects who can be diagnosed or identified as having serotonin receptor-associated cancer are subjects who have cancer (e.g., subjects identified as having cancer), or subjects suspected of having cancer. Subjects can be diagnosed or identified as having serotonin receptor-associated cancer based on screening of patient cancer samples (e.g., tumor biopsies containing immune cells or isolated immune cells). Serotonin receptor expression (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7) can be assessed in an immune cell in a sample isolated from a subject using standard techniques known in the art, such as immunohistochemistry, western blot analysis, quantitative RT-PCR, RNA sequencing, fluorescent in situ hybridization, cDNA microarray, and droplet digital PCR. Serotonin receptor expression can be assessed by comparing measurements obtained from samples isolated from a subject to measurements of serotonin receptor expression obtained from a reference sample (e.g., an immune cell of the same type from a subject that does not have cancer or a cell that does not express serotonin receptor, e.g., a HEK cell). Reference samples can be obtained from healthy subjects (e.g., subjects without cancer), or they can be obtained from databases in which average measurements of serotonin receptor expression are cataloged for immune cells from healthy subjects (e.g., subjects without cancer). 
     Subjects are diagnosed or identified as having serotonin receptor-associated cancer if the expression of one or more serotonin receptors (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7) is increased in the sample isolated from the subject (e.g., immune cell) compared to the reference sample. An increase of serotonin receptor expression of 1.1-fold or more (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0-fold or more) in the sample isolated from the subject compared to the reference indicates that the subject has serotonin receptor-associated cancer. Subjects can also be diagnosed or identified as having serotonin receptor-associated cancer (e.g., a cancer in which serotonin receptor is functional in immune cells) by contacting an immune cell isolated from the subject with a serotonin receptor antagonist and evaluating pro-inflammatory cytokine production (e.g., IL-8 secretion). An increase in pro-inflammatory cytokine production by 10% or more (e.g., 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or more) indicates that the immune cell expresses a functional serotonin receptor (e.g., the subject has a serotonin receptor-associated cancer). Serotonin receptors can also be evaluated in vivo using radioligand labeling with PET/SPECT radioligands, such as those described in Paterson et al., Med Res Rev. 33:54, 2013. Subjects diagnosed or identified as having serotonin receptor-associated cancer can be treated with the methods and compositions described herein (e.g., serotonin receptor inhibitors). Subjects with cancer can also be treated with the methods and compositions described herein if an immune cell from the subject (e.g., an immune cell from a tumor biopsy or an isolated immune cell) is found to express one or more serotonin receptors (e.g., one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7). 
     The methods described herein also include methods of predicting patient response (e.g., the response of cancer in a subject) to serotonin receptor inhibitors in order to determine whether serotonin receptor inhibitors can be used for cancer treatment. In some embodiments, a sample (e.g., a tumor biopsy containing immune cells or an isolated immune cell) is isolated from a subject and contacted with one or more serotonin receptor inhibitors or serotonin receptor-specific inhibitors (e.g., samples are cultured and contacted with one or more inhibitors in vitro). The response of the sample to the one or more serotonin receptor inhibitors or serotonin receptor-specific inhibitors is evaluated to predict response to treatment. Responses that are evaluated include cancer cell or tumor growth, cancer cell or tumor proliferation, cancer cell or tumor migration, cancer cell or tumor metastasis, cancer cell or tumor invasion, cancer cell or tumor autophagy, cancer cell or tumor death, immune cell migration, proliferation, recruitment, tumor homing, tumor egress, differentiation, activation, polarization, cytokine production, degranulation, maturation, ADCC, ADCP, antigen presentation, or immune cell serotonin receptor expression. A decrease of at least 5% or more (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or more) in cancer cell or tumor growth, cancer cell or tumor proliferation, cancer cell or tumor migration, cancer cell or tumor metastasis, cancer cell or tumor invasion, immune cell tumor egress, or immune cell serotonin receptor expression in treated cells compared to untreated or control-treated cells, or an increase of at least 5% or more (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or more) in cancer cell or tumor death, cancer cell autophagy, immune cell migration, proliferation, recruitment, differentiation, activation, polarization, pro-inflammatory cytokine production, tumor homing degranulation, maturation, ADCC, ADCP, or antigen presentation in treated cells compared to untreated or control-treated cells indicates that the cancer would respond to treatment with a serotonin receptor inhibitor. 
     The methods used above to diagnose or identify a subject with serotonin receptor-associated cancer can also be used to predict patient response (e.g., the response of cancer in a subject) to treatment with a serotonin receptor inhibitor. If the expression of one or more serotonin receptors (e.g., expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, or HTR7) is increased in a sample isolated from a subject compared to a reference (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0-fold or more higher in the sample compared to the reference), the subject can be predicted to respond to treatment with a serotonin receptor inhibitor. Subjects predicted to respond to treatment with a serotonin receptor inhibitor or serotonin receptor-specific inhibitor can be treated using the methods and compositions described herein (e.g., serotonin receptor inhibitors). 
     Methods of Treatment 
     Administration 
     An effective amount of a serotonin receptor inhibitor described herein for treatment of cancer can be administered to a subject by standard methods. For example, the agent can be administered by any of a number of different routes including, e.g., intravenous, intradermal, subcutaneous, percutaneous injection, oral, transdermal (topical), or transmucosal. The serotonin receptor inhibitor can be administered orally or administered by injection, e.g., intramuscularly, or intravenously. The most suitable route for administration in any given case will depend on the particular agent administered, the patient, the particular disease or condition being treated, pharmaceutical formulation methods, administration methods (e.g., administration time and administration route), the patients age, body weight, sex, severity of the diseases being treated, the patient&#39;s diet, and the patient&#39;s excretion rate. The agent can be encapsulated or injected, e.g., in a viscous form, for delivery to a chosen site, e.g., a tumor site. The agent can be provided in a matrix capable of delivering the agent to the chosen site. Matrices can provide slow release of the agent and provide proper presentation and appropriate environment for cellular infiltration. Matrices can be formed of materials presently in use for other implanted medical applications. The choice of matrix material is based on any one or more of: biocompatibility, biodegradability, mechanical properties, and cosmetic appearance and interface properties. One example is a collagen matrix. 
     The agent (e.g., serotonin receptor inhibitor, e.g., polypeptide, small molecule, nucleic acid, or antibody) can be incorporated into pharmaceutical compositions suitable for administration to a subject, e.g., a human. Such compositions typically include the agent and a pharmaceutically acceptable carrier. As used herein the term “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances are known. Except insofar as any conventional media or agent is incompatible with the active compound, such media can be used in the compositions of the invention. Supplementary active compounds can also be incorporated into the compositions. 
     A pharmaceutical composition can be formulated to be compatible with its intended route of administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. 
     Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. 
     Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a serotonin receptor inhibitor described herein) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. 
     Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. 
     Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. 
     The active compounds can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. 
     Nucleic acid molecule agents described herein can be administered directly (e.g., therapeutic mRNAs) or inserted into vectors used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see U.S. Pat. No. 5,328,470) or by stereotactic injection (see, e.g., Chen et al., PNAS 91:3054 1994). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can include a slow release matrix in which the gene delivery vehicle is embedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells which produce the gene delivery system. 
     The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. 
     Methods of formulating pharmaceutical agents are known in the art, e.g., Niazi, Handbook of Pharmaceutical Manufacturing Formulations (Second Edition), CRC Press 2009, describes formulation development for liquid, sterile, compressed, semi-compressed and OTC forms. Transdermal and mucosal delivery, lymphatic system delivery, nanoparticles, controlled drug release systems, theranostics, protein and peptide drugs, and biologics delivery are described in Wang et al., Drug Delivery: Principles and Applications (Second Edition), Wiley 2016; formulation and delivery of peptide and protein agent is described, e.g., in Banga, Therapeutic Peptides and Proteins: Formulation, Processing, and Delivery Systems (Third Edition), CRC Press 2015. 
     Local Administration 
     The serotonin receptor inhibitors described herein can be administered locally, e.g., to the site of cancer in the subject. Examples of local administration include epicutaneous, inhalational, intra-articular, intrathecal, intravaginal, intravitreal, intrauterine, intra-lesional administration, lymph node administration, intratumoral administration and administration to a mucous membrane of the subject, wherein the administration is intended to have a local and not a systemic effect. As an example, for the treatment of a cancer described herein, the serotonin receptor inhibitor may be administered locally (e.g., intratumorally) in a compound-impregnated substrate such as a wafer, microcassette, or resorbable sponge placed in direct contact with the affected tissue. Alternatively, the serotonin receptor inhibitor is infused into the brain or cerebrospinal fluid using standard methods. As one example, a pulmonary cancer described herein may be treated, for example, by administering the serotonin receptor inhibitor locally by inhalation, e.g., in the form of an aerosol spray from a pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide or a nebulizer. A serotonin receptor inhibitor for use in the methods described herein can be administered to a lymph node or at the site of a tumor, e.g., intratumorally. In certain embodiments, the agent is administered to a mucous membrane of the subject. 
     Combination Therapy 
     The serotonin receptor inhibitors described herein may be administered in combination with one or more additional therapies (e.g., 1, 2, 3 or more additional therapeutic agents). The two or more agents can be administered at the same time (e.g., administration of all agents occurs within 15 minutes, 10 minutes, 5 minutes, 2 minutes or less). The agents can also be administered simultaneously via co-formulation. The two or more agents can also be administered sequentially, such that the action of the two or more agents overlaps and their combined effect is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two or more treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, local routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination can be administered locally in a compound-impregnated microcassette. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after the second therapeutic agent. 
     For use in treating cancer, the second agent may be a checkpoint inhibitor, a chemotherapeutic drug, a biologic drug, a biologic cancer agent (e.g., an agent listed in Table 7), a cancer-specific agent (e.g., an agent listed in Table 8), a non-drug therapy, CAR-T therapy, a neurotransmission modulator, or a neuronal growth factor modulator. In one embodiment, the inhibitor of checkpoint is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, e.g., humanized or fully human. In other embodiments, the inhibitor of checkpoint is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein. In other embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein. In one embodiment, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody such as ipilimumab or tremelimumab). In one embodiment, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab; pembrolizumab; pidilizumab/CT-011). In one embodiment, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A/RG7446; MED14736; MSB0010718C; BMS 936559). In one embodiment, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2/Ig fusion protein such as AMP 224). In one embodiment, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAGS, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. The second agent may also be an anti-angiogenic drug, e.g., an anti-VEGF antibody, or the second agent may be an oncolytic agent e.g., a chemotherapy, a drug that targets cancer metabolism, an antibody that marks a cancer cell surface for destruction, e.g., rituximab or trastuzumab, an antibody-drug conjugate, e.g., trastuzumab emtansine, a cell therapy, or other commonly-used anti-neoplastic agent. 
     Dosing 
     Subjects that can be treated as described herein are subjects with cancer or at risk of developing cancer. The cancer may be a primary tumor or a metastasized tumor. In some embodiments, the cancer is a serotonin receptor-associated cancer. Subjects who can be treated with the methods disclosed herein include subjects who have had one or more tumors resected, received chemotherapy or other pharmacological treatment for the cancer, received radiation therapy, and/or received other therapy for the cancer. Subjects who have never previously been treated for cancer can also be treated using the methods described herein. 
     In some embodiments, the agent is administered in an amount and for a time effective to result in one of (or more, e.g., 2 or more, 3 or more, 4 or more of): (a) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) reduced tumor migration, (h) reduced tumor invasion, (i) reduced tumor volume, (j) decreased tumor recurrence, (k) increased survival of subject, (l) increased progression free survival of subject. 
     The methods described herein may include a step of selecting a treatment for a patient. The method includes (a) identifying (e.g., diagnosing) a patient who has cancer or is at risk of developing cancer, and (b) selecting a serotonin receptor inhibitor, e.g., a serotonin receptor inhibitor described herein, to treat the condition in the patient. In some embodiments, the method includes administering the selected treatment to the subject. In some embodiments, a patient is identified as having cancer based on imaging (e.g., MRI, CT, or PET scan), biopsy, or blood sample (e.g., detection of blood antigen markers, circulating tumor DNA (e.g., by PCR). In some embodiments, a patient is identified as having cancer after presenting with one or more symptoms of a paraneoplastic syndrome (e.g., fever, auto-antibodies directed against nervous system proteins, ataxia, dizziness, nystagmus, difficulty swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech memory loss, vision loss, sleep disturbances, dementia, seizures, dysgeusia, cachexia, anemia, itching, or sensory loss in the limbs). In some embodiments, a patient presents with symptoms of paraneoplastic syndrome and is then identified as having cancer based on imaging (e.g., CT, MRI, or PET scans). 
     The method may also include (a) identifying (e.g., diagnosing) a patient who has a neoplasm, (b) optionally evaluating the neoplasm for innervation, and (c) selecting a serotonin receptor inhibitor (e.g., a serotonin receptor inhibitor described herein) to treat the patient if the neoplasm is highly innervated (e.g., if the level of innervation is at least 10% higher (e.g., at least 20%, 30%, 40%, 50%, 60%, 70%, 80% higher) than the level of innervation in control tissue, e.g., non-cancerous tissue of the same subject). Innervation may be measured by staining tissue sections for neural markers e.g., immuno-histochemical staining for tyrosine hydroxylase, vesicular acetylcholine transporter; NGF-Inducible Large External glycoprotein, choline acetyltransferase, parvalbumin, neurofilament protein, Synapsin, synaptophysin, NeuN, NSE, MAP2, Beta III tubulin, 160 kD Neurofilament medium/200 kD Neurofilament Heavy, NSE, PSD93/PSD95, Doublecortin (DCX), c-fos, PSA-NCAM, NeuroD or Beta2, Tau, Calbindin-D28k, Calretinin, Neurofilament Protein (NFP), Glial fibrillary acidic protein (GFAP), S100β, Vimentin and CNPase; or by staining tissue sections with cell-identifying stains, e.g., H&amp;E stain, Nissl Stain, Cresyl violet, Neutral red, Thionine and Toluidine blue, Luxol Fast blue stain, Weigert&#39;s Chromium hematoxylin method, Page&#39;s iron-eriochrome cyanine R, Dextran Conjugates (Fluorescein, Tetramethylrhodamine, Texas Red, Rhodamine Green), Hydrazides &amp; Biocytins, Isolectin GS-1B4 conjugates, Golgi silver stain, or myelin stain; or by imaging the nervous system, e.g., by MRI, CT, PET, EEG, EMG, Myelogram, or magnetoencephalography. In some embodiments, the neoplasm is selected from: head and neck squamous cell carcinoma, adenoid cystic carcinoma, lymphoma, rhabdomyosarcoma, biliary tract cancer, gastric cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, skin cancer (e.g., melanoma), renal cell carcinoma, or colorectal cancer. In some embodiments, the cancer is a cancer listed in Table 7 or 8. In some embodiments, the neoplasm is derived from a secretory tissue, glandular tissue, or endocrine or hormonal tissue. 
     In one embodiment, the method includes (a) identifying (e.g., diagnosing) a patient who has a neoplasm, (b) optionally evaluating the neoplasm for perineural invasion, and (c) selecting a serotonin receptor inhibitor to treat the patient if the neoplasm exhibits perineural invasion. In some embodiments, the neoplasm is selected from: head and neck squamous cell carcinoma, adenoid cystic carcinoma, lymphoma, rhabdomyosarcoma, biliary tract cancer, gastric cancer, pancreatic cancer, and prostate cancer. 
     In one embodiment, the method includes (a) identifying (e.g., diagnosing) a patient who has a neoplasm, (b) optionally evaluating the subject for metastasis to brain or spinal cord, and (c) selecting a serotonin receptor inhibitor to treat the patient if the neoplasm exhibits metastasis to brain or spinal cord. In some embodiments, the neoplasm is a lung cancer, breast cancer, skin cancer (e.g., melanoma), lymphoma, renal cell carcinoma, GI tract cancer, prostate cancer, or colorectal cancer. 
     In one embodiment, the method includes (a) identifying (e.g., diagnosing) a patient who has cancer, (b) optionally evaluating the subject for serotonin receptor overexpression, and (c) selecting a serotonin receptor inhibitor to treat the patient if the cancer is associated with serotonin receptor overexpression in immune cells (e.g., if the patient has serotonin receptor-associated cancer). In some embodiments, the neoplasm is a lung cancer, breast cancer, skin cancer (e.g., melanoma), lymphoma, renal cell carcinoma, GI tract cancer, prostate cancer, ovarian cancer, uterine cancer, head and neck cancer, esophageal cancer, mesothelioma or colorectal cancer. Serotonin receptor expression can be measured in an immune cell sample collected from a subject using standard techniques known in the art, such as immunohistochemistry, western blot analysis, quantitative RT-PCR, RNA sequencing, fluorescent in situ hybridization, cDNA microarray, and droplet digital PCR. An immune cell sample can be evaluated for increased expression of one or more serotonin receptors (e.g., one or more serotonin receptors listed in Table 1) by comparison to a reference sample (e.g., an immune cell of the same type from a patient not diagnosed with cancer). 
     In some embodiments, the method includes administering the selected treatment to the subject. 
     The method may also include a step of assessing the subject for a parameter of cancer progression or remission, e.g., assessing the subject for one or more (e.g., 2 or more, 3 or more, 4 or more) of: primary tumor size (e.g., by imaging), number of metastases (e.g., by imaging or biopsy), cell death in situ (e.g., by biopsy), blood antigen markers (e.g., by ELISA), circulating tumor DNA (e.g., by PCR), or function of the affected organ (e.g., by a test of circulating enzymes for liver, albuminuria for kidney, lung capacity for lung, etc.). 
     In some embodiments, the tumor is treated with a serotonin receptor inhibitor and a second therapeutic agent. The second therapeutic agent can be selected based on tumor type, tumor tissue of origin, tumor stage, tumor innervation, or mutations in genes expressed by the tumor. 
     In certain embodiments, a serotonin receptor inhibitor administered according to the methods described herein does not have a direct effect on the central nervous system (CNS) or gut. Any effect on the CNS or gut is reduced compared to the effect observed if the serotonin receptor inhibitor is administered directly to the CNS or gut. In some embodiments, direct effects on the CNS or gut are avoided by modifying the serotonin receptor inhibitor not to cross the BBB, as described herein above, or administering the agent locally to a subject. 
     Subjects with cancer or at risk of developing cancer are treated with an effective amount of a serotonin receptor inhibitor. The methods described herein also include contacting immune cells with an effective amount of a serotonin receptor inhibitor. In some embodiments, an effective amount of a serotonin receptor inhibitor is an amount sufficient to increase or decrease lymph node innervation, tumor innervation, the development of HEVs or TLOs, immune cell migration, proliferation, recruitment, lymph node homing, lymph node egress, differentiation, tumor homing, tumor egress, activation, polarization, cytokine production, degranulation, maturation, ADCC, ADCP, or antigen presentation. In some embodiments, an effective amount of a serotonin receptor inhibitor is an amount sufficient to increase or decrease tumor innervation or nerve activity in a tumor. In some embodiments, an effective amount of a serotonin receptor inhibitor is an amount sufficient to treat the cancer or tumor, cause remission, reduce tumor growth, volume, metastasis, migration, invasion, proliferation, or number, increase cancer cell death, increase time to recurrence, or improve survival. 
     The methods described herein may also include a step of assessing the subject for a parameter of immune response, e.g., assessing the subject for one or more (e.g., 2 or more, 3 or more, 4 or more) of: Th2 cells, T cells, circulating monocytes, neutrophils, peripheral blood hematopoietic stem cells, macrophages, mast cell degranulation, activated B cells, NKT cells, macrophage phagocytosis, macrophage polarization, antigen presentation, immune cell activation, immune cell proliferation, immune cell lymph node homing or egress, T cell differentiation, immune cell recruitment, immune cell migration, lymph node innervation, dendritic cell maturation, HEV development, TLO development, or cytokine production. In embodiments, the method includes measuring a cytokine or marker associated with the particular immune cell type, as listed in Table 4 (e.g., performing an assay listed in Table 4 for the cytokine or marker). In some embodiments, the method includes measuring a chemokine, receptor, or immune cell trafficking molecule, as listed in Tables 5 and 6 (e.g., performing an assay to measure the chemokine, marker, or receptor). The assessing may be performed after the administration, before the first administration and/or during a course a treatment, e.g., after a first, second, third, fourth or later administration, or periodically over a course of treatment, e.g., once a month, or once every 3 months. In one embodiment, the method includes assessing the subject prior to treatment or first administration and using the results of the assessment to select a subject for treatment. In certain embodiments, the method also includes modifying the administering step (e.g., stopping the administration, increasing or decreasing the periodicity of administration, increasing or decreasing the dose of the serotonin receptor inhibitor) based on the results of the assessment. For example, in embodiments where increasing a parameter of immune response described herein is desired (e.g., cancer or infectious disease-related embodiments where, e.g., an increase in Th2 cells is desired), the method includes stopping the administration if a marker of Th2 cells is not increased at least 5%, 10%, 15%, 20%, 30%, 40%, 50% or more; or the method includes increasing the periodicity of administration if the marker of Th2 cells is not increased at least 5%, 10%, 15%, 20%, 30%, 40%, 50% or more; or the method includes increasing the dose of the serotonin receptor inhibitor if the marker of Th2 cells is not increased at least 5%, 10%, 15%, 20%, 30%, 40%, 50% or more. 
     In certain embodiments, immune effects (e.g., immune cell activities) are modulated in a subject (e.g., a subject having a cancer or inflammatory or autoimmune condition) or in a cultured cell by at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, compared to before an administration, e.g., of a dosing regimen, of a serotonin receptor inhibitor such as those described herein. In certain embodiments, the immune effects are modulated in the subject or a cultured cell between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%, between 50-100%, between 100-500%. The immune effects described herein may be assessed by standard methods. 
     The serotonin receptor inhibitors described herein are administered in an amount (e.g., an effective amount) and for a time sufficient to effect one of the outcomes described above. The serotonin receptor inhibitor may be administered once or more than once. The serotonin receptor inhibitor may be administered once daily, twice daily, three times daily, once every two days, once weekly, twice weekly, three times weekly, once biweekly, once monthly, once bimonthly, twice a year, or once yearly. Treatment may be discrete (e.g., an injection) or continuous (e.g., treatment via an implant or infusion pump). Subjects may be evaluated for treatment efficacy 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months or more following administration of a serotonin receptor inhibitor depending on the serotonin receptor inhibitor and route of administration used for treatment. Depending on the outcome of the evaluation, treatment may be continued or ceased, treatment frequency or dosage may change, or the patient may be treated with a different serotonin receptor inhibitor. Subjects may be treated for a discrete period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) or until the disease or condition is alleviated, or treatment may be chronic depending on the severity and nature of the disease or condition being treated. 
     Kits 
     The invention also features a kit including (a) a pharmaceutical composition including a serotonin receptor inhibitor described herein, and (b) instructions for administering the pharmaceutical composition to treat cancer. 
     EXAMPLES 
     The following examples are provided to further illustrate some embodiments of the present invention, but are not intended to limit the scope of the invention; it will be understood by their exemplary nature that other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used. 
     Example 1—Identification of Serotonin Receptor Expression in Macrophages 
     CD14+ monocytes were isolated from human PBMCs using negative magnetic bead selection (Stemcell Technologies) on day 0. Cells were cultured two days with M-CSF to differentiate monocytes to macrophages. On day 3, macrophages were polarized to M1-like macrophages with IFNγ and LPS; and M2-like macrophages with IL4, IL10, and TGF8. Cells were harvested on day 6. The cells were lysed and RNA was extracted using an RNA extraction kit (Qiagen). qPCR was performed using integrated fluidic circuits (IFCs) run on a real-time PCR machine (Fluidigm) with primers specific for HTR2B, HTR2C, and HTR7 (Life Technologies). Gene expression was normalized to HPRT1. Expression level was calculated by 2{circumflex over ( )}(−delta CT), where delta CT is (GOI Ct-HPRT Ct). 
     Gene expression for HTR2B and HTR7 in M1-like and M2-like macrophages was determined. Both HTR2B and HTR7 expression levels were higher on M1-like macrophages, as shown in Table 17 below. 
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 EXPRESSION OF SEROTONIN RECEPTORS  
               
               
                 IN M1- AND M2-LIKE MACROPHAGES 
               
            
           
           
               
               
               
            
               
                   
                   
                 Expression Level  
               
               
                 Cell Type  
                 Gene Name  
                 (Relative to HPRT1) 
               
               
                   
               
               
                 M1-like Macrophages  
                 HTR2B (Entrez: 3357)  
                 0.7687  
               
               
                 M2-like Macrophages 
                 HTR2B (Entrez: 3357) 
                 0.0177  
               
               
                 M1-like Macrophages  
                 HTR7 (Entrez: 3363)  
                 0.0162  
               
               
                 M2-like Macrophages  
                 HTR7 (Entrez: 3363) 
                 0.0068 
               
               
                   
               
            
           
         
       
     
     Example 2—Examination of Target Expression in Immune Cells 
     The Immunological Genome Project (ImmGen) dataset of mouse immune cell gene expression (www.immgen.org) was examined for expression of serotonin receptors in different cell subsets. The expression data was generated by RNAseq on sorted mouse immune cells and quantified using the DESeq2 algorithm (Love et al., Genome Biology 15:550, 2014). The output of the DESeq2 algorithm was expression level, in arbitrary units, normalized to an internal factor derived from the sequencing depth of the sample. 
     Mouse cells were sorted from MC38 (C57BL6 murine colon adenocarcinoma cells) syngeneic tumors. Cells were sorted on an Aria sorter using the following markers: dendritic cells (CD45+ live CD19-CD3-CD11 b+CD11c+), neutrophils (CD45+ live CD19-CD3-CD11 b+Ly6c lo Ly6G hi), monocytes (CD45+ live CD19-CD3-CD11b+Ly6c hi F4/80 lo), M2-like macrophages (CD45+ live CD19-CD3-CD11b+F4/80 hi). Cells were lysed and RNA was extracted using the RNeasy Mini Kit (Qiagen). RNA was submitted for Smart-Seq2 (Illumina). Median based normalization was performed with DESeq2. 
     HTR2B, HTR2C and HTR7 were found to be expressed on multiple types of myeloid lineage cells, including macrophages and dendritic cells, as shown in Table 18 below. 
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 EXPRESSION OF SEROTONIN  
               
               
                 RECEPTORS IN MOUSE IMMUNE CELLS 
               
            
           
           
               
               
               
            
               
                   
                   
                 Expression  
               
               
                   
                   
                 Level (Relative  
               
               
                 Cell Type  
                 Gene Name  
                 to HPRT1) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Splenic Dendritic Cells 
                 HTR2B (Entrez: 3357)  
                 22.12  
               
               
                 Peritoneal Macrophages  
                 HTR2B (Entrez: 3357)  
                 6.51  
               
               
                 Alveolar Macrophages 
                 HTR2C (Entrez: 3358)  
                 12.87 
               
               
                 Alveolar Macrophages  
                 HTR2C (Entrez: 3358)  
                 329.65  
               
               
                 Splenic Dendritic Cells 
                 HTR7 (Entrez: 3363)  
                 229.74  
               
               
                 Tumor-infiltrating Dendritic  
                 HTR7 (Entrez: 3363)  
                 89.49  
               
               
                 Cells 
                   
                   
               
               
                 Tumor-infiltrating M2  
                 HTR7 (Entrez: 3363)  
                 114.87 
               
               
                 Macrophages 
                   
                   
               
               
                 Tumor-infiltrating Monocytes 
                 HTR7 (Entrez: 3363) 
                 122.35  
               
               
                 Tumor-infiltrating Neutrophils  
                 HTR7 (Entrez: 3363)  
                 68.70 
               
               
                   
               
            
           
         
       
     
     Example 3—Modulation of Serotonin Receptors with Serotonin Receptor Agonists Decreases IL8 Secretion in Immune Cells 
     CD14+ monocytes were isolated from human PBMCs using negative magnetic bead selection (Stemcell Technologies) on day 0. Cells were cultured with M-CSF to differentiate monocytes to macrophages. On day 6, cells were treated with LP44 (high affinity 5-HT7 agonist), BW 723C86 hydrochloride (5-HT2B agonist), MK 212 hydrochloride (5-HT2C agonist) (Sigma-Aldrich), at concentrations 1 μM and 10 μM overnight. Supernatant was collected and bead-based immunoassays (Biolegend) were performed to detect changes in cytokine secretion. 
     Across multiple human donors, secretion of the inflammatory cytokine, IL8, by macrophages was decreased after addition of each of the HTR2B, HTR2C, and HTR7 agonists, as show in Table 18 below. 
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 IL8 SECRETION BY MACROPHAGES  
               
               
                 INCUBATED WITH SEROTONIN RECEPTOR AGONISTS  
               
            
           
           
               
               
            
               
                   
                 Fold change of IL-8  
               
               
                   
                 (Normalized to Macs + LPS  
               
               
                 Sample  
                 with no compound treatment) 
               
               
                   
               
            
           
           
               
               
            
               
                 Macs alone  
                 1.00  
               
               
                 Macs + LP44 (1 μM)  
                 0.340  
               
               
                 Macs + LP44 (10 μM) 
                 0.427  
               
               
                 Macs + BW723086 (1 μM) 
                 0.670  
               
               
                 Macs + BW723086 (10 μM)  
                 0.508  
               
               
                 Macs + MK212 (1 μM) 
                 0.502 
               
               
                 Macs + MK212 (10 μM) 
                 0.484 
               
               
                   
               
            
           
         
       
     
     Example 4—Treatment of Cancer Using a Serotonin Receptor Inhibitor 
     According to the methods disclosed herein, a physician of skill in the art can treat a patient, such as a human patient with a solid tumor that is a candidate for immunotherapy (e.g., the patient has substantial immune cell infiltration (e.g., infiltration of T cells, dendritic cells, or myeloid cells, e.g., macrophages) into the tumor as assessed by histological analysis of a biopsy), so as to inhibit solid tumor growth or reduce tumor volume. The method of treatment can include diagnosing or identifying a patient as a candidate for treatment with a serotonin receptor inhibitor based on serotonin receptor expression (e.g., the expression of one or more serotonin receptors listed in Table 1, e.g., HTR1F, HTR2B, HTR2C, HTR3A, HTR6, and/or HTR7) in a biopsy (e.g., a biopsy containing immune cells, e.g., T cells, dendritic cells, monocytes, macrophages, or MDSCs), or in isolated immune cells (e.g., T cells, dendritic cells, monocytes, macrophages, or MDSCs). For example, a tissue sample or immune cells can be collected from a patient&#39;s cancer and analyzed for RNA expression by qPCR or RNAseq analysis, and the cancer can be found to express high levels of one or more serotonin receptors. To treat the patient, a physician of skill in the art can administer a serotonin receptor inhibitor that decreases serotonin receptor expression or serotonin receptor activity (e.g., a serotonin receptor inhibitory antibody or a serotonin receptor small molecule inhibitor). The serotonin receptor inhibitor can be administered locally (e.g., injected into the tumor or tumor microenvironment) to decrease tumor growth or volume. The serotonin receptor inhibitor is administered in a therapeutically effective amount, such as from 10 μg/kg to 500 mg/kg (e.g., 10 μg/kg, 100 μg/kg, 500 μg/kg, 1 mg/kg, 10 mg/kg, 50 mg/kg, 100 mg/kg, 250 mg/kg, or 500 mg/kg). In some embodiments, the serotonin receptor inhibitor is administered bimonthly, once a month, once every two weeks, or at least once a week or more (e.g., 1, 2, 3, 4, 5, 6, or 7 times a week or more). 
     The serotonin receptor inhibitor activates the patient&#39;s immune cells (e.g., increases macrophage cytokine production of one or more pro-inflammatory cytokines, e.g., IL-8). The serotonin receptor inhibitor is administered to the patient in an amount sufficient to decrease tumor burden, increase progression free survival, or increase pro-inflammatory cytokine levels by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more). Cytokine production can be assessed by collecting a blood sample from the patient and evaluating one or more pro-inflammatory cytokines (e.g., IL-2, IFNγ, IL-5, IL-6, or IL-8). The blood sample can be collected one day or more after administration of the serotonin receptor inhibitor (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 14, 21, or 30 or more days after administration). The blood sample can be compared to a blood sample collected from the patient prior to administration of the serotonin receptor inhibitor (e.g., a blood sample collected earlier the same day, 1 day, 1 week, 2 weeks, one month or more before administration of the serotonin receptor inhibitor). Tumor burden can be assessed using standard imaging methods (e.g., digital radiography, positron emission tomography (PET) scan, computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan). Images from before and after administration of the serotonin receptor inhibitor can be compared to evaluate the efficacy of the treatment. A finding of a reduction in the total number of tumors, number of primary tumors, volume of tumors, positive lymph nodes, or distant metastases, or an increase in progression free survival indicates that the serotonin receptor inhibitor has successfully treated the cancer. 
     Example 5—Polarize Macrophages to M1 for Tumor Immunotherapy Using a Serotonin Receptor Inhibitor 
     According to the methods disclosed herein, a physician of skill in the art can treat a patient, such as a human patient with a solid tumor that is non-responsive to immunotherapy, so as to inhibit solid tumor growth or reduce tumor volume. A tumor can be considered non-responsive to immunotherapy if a prior course of treatment with a checkpoint inhibitor antibody, e.g., anti-PDL1, was unsuccessful, or if the tumor is categorized as “cold”, “immune excluded”, or “immune desert” based on the absence of active CD8 lymphocytes within the tumor or the presence of M0/M2 monocytes, macrophages, or MDSCs as assessed by histology or transcriptional profiling of a tumor biopsy. The method of treatment can include diagnosing or identifying a patient as having a solid tumor that is non-responsive to immunotherapy based on medical history or biopsy results conducted by the physician or a skilled laboratory technician. 
     To treat the patient, a physician of skill in the art can administer to the human patient a serotonin receptor inhibitor (e.g., a serotonin receptor inhibitory antibody or a small molecule serotonin receptor inhibitor) that increases macrophage polarization toward an M1 phenotype (e.g., an agent that increases macrophage production of pro-inflammatory cytokines and reverses local immune suppression). The serotonin receptor inhibitor is administered locally to the tumor (e.g., intratumoral injection) to decrease tumor growth or reduce tumor burden. The serotonin receptor inhibitor is administered in a therapeutically effective amount, such as from 10 μg/kg to 500 mg/kg (e.g., 10 μg/kg, 100 μg/kg, 500 μg/kg, 1 mg/kg, 10 mg/kg, 50 mg/kg, 100 mg/kg, 250 mg/kg, or 500 mg/kg). In some embodiments, the serotonin receptor inhibitor is administered bimonthly, once a month, once every two weeks, or at least once a week or more (e.g., 1, 2, 3, 4, 5, 6, or 7 times a week or more). 
     The serotonin receptor inhibitor increases macrophage polarization toward an M1 phenotype (e.g., increases macrophage production of pro-inflammatory cytokines, such as IL-8). The serotonin receptor inhibitor is administered to the patient in an amount sufficient to decrease tumor burden, slow tumor growth, increase M1 polarization by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more). Macrophage polarization can be assessed by collecting a tumor biopsy sample from the patient and evaluating one or more pro-inflammatory cytokines (e.g., IL-12, TNFα, IL-6, IL-8, IL-1B, MCP-1 or CCL2) or antigen presentation markers (e.g., CD11c, CD11b, HLA molecules (e.g., MHC-II), CD40, B7, CD80 or CD86) using flow cytometry or immunohistochemistry. The biopsy can be collected one day or more after administration of the serotonin receptor inhibitor (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 14, 21, 30, or 60 or more days after administration). The biopsy can be compared to a biopsy collected from the patient prior to administration of the serotonin receptor inhibitor (e.g., a biopsy collected earlier the same day, 1 day, 1 week, 2 weeks, one month or more before administration of the serotonin receptor inhibitor). Tumor burden and tumor growth can be assessed using standard imaging methods (e.g., digital radiography, positron emission tomography (PET) scan, computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan). Images from before and after administration of the serotonin receptor inhibitor can be compared to evaluate the efficacy of the treatment. A finding of a reduction in the total number of tumors, number of primary tumors, volume of tumors, growth of tumors, positive lymph nodes, or distant metastases, or an increase in progression free survival, cancer cell death, or markers of M1 polarization indicates that the serotonin receptor inhibitor has successfully improved the patient&#39;s condition and treated the cancer. 
     Example 6—Identification of Serotonin Receptors in T Cells 
     Naïve CD4+ and CD8+ T cells were isolated from human PBMCs using negative magnetic bead selection (Stemcell Technologies). Cells were activated with human CD3/CD28 T cell activator (StemCell). Cells were lysed and RNA was extracted (Qiagen). 
     RNA was sequenced at the Broad Technology Labs (BTL) at the Broad Institute using their Smart-Seq2 protocol, a protocol for full-length transcript sequencing from single cells. Smart-Seq2 libraries were sequenced on a high output sequence machine (Illumina) using a high out-put flow cell and reagent kit to generate 2×25 bp reads (plus dual index reads). Further details are available through the BTL, but in brief, reads were demultiplexed and aligned utilizing an ultrafast RNAseq alignment algorithm (Dobin et al., Bioinformatics. 29:15, 2013) with the following parameters: --twopassMode Basic, 
     --alignIntronMax 1000000, --alignMatesGapMax 1000000, --sjdbScore 2, --quantMode TranscriptomeSAM, and --sjdbOverhang 24. 
     Quantification of individual read counts was performed using the DESeq2 algorithm (Love et al., Genome Biology 15:550, 2014), a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enabled a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The output of the DESeq2 algorithm was an expression level, in arbitrary units, normalized to an internal factor derived from the sequencing depth of the sample. 
     Gene expression for select serotonin receptors (HTRs) was detected in different T cell subsets, as shown in Table 20 below. 
     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 HTR EXPRESSION IN T CELL SUBSETS  
               
            
           
           
               
               
               
            
               
                   
                   
                 Expression Level  
               
               
                 Cell Type 
                 Gene Name 
                 (DESeq2 normalized) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Human aCD3/aCD28  
                 HTR1E (Entrez: 3354)  
                 0.3 
               
               
                 activated CD8+ T-Cells  
                   
                   
               
               
                 Human Naïve CD8+ 
                 HTR1F (Entrez: 3355) 
                 0.65  
               
               
                 Human Naïve CD4+ 
                 HTR1F (Entrez: 3355) 
                 4.9  
               
               
                 Human aCD3/aCD28  
                 HTR1F (Entrez: 3355)  
                 0.39  
               
               
                 activated CD8+ T-Cells  
                   
                   
               
               
                 Human Naïve CD8+ 
                 HTR2B (Entrez: 3357)  
                 1.2  
               
               
                 Human Naïve CD4+ 
                 HTR2B (Entrez: 3357)  
                 0.75  
               
               
                 Human aCD3/aCD28  
                 HTR2B (Entrez: 3357)  
                 0.6  
               
               
                 activated CD8+ T-Cells  
                   
                   
               
               
                 Human aCD3/aCD28  
                 HTR2B (Entrez: 3357) 
                 0.42  
               
               
                 activated CD4+ T-Cells 
                   
                   
               
               
                 Human Naïve CD8+ 
                 HTR3A (Entrez: 3359)  
                 0.97  
               
               
                 Human Naïve CD8+ 
                 HTR6 (Entrez: 3362)  
                 1.07  
               
               
                 Human Naïve CD4+ 
                 HTR6 (Entrez: 3362)  
                 3.98  
               
               
                 Human aCD3/aCD28  
                 HTR6 (Entrez: 3362)  
                 0.19  
               
               
                 activated CD8+T-Cells  
                   
                   
               
               
                 Human aCD3/aCD28  
                 HTR6 (Entrez: 3362) 
                 0.74  
               
               
                 activated CD4+ T-Cells  
                   
                   
               
               
                 Human Naïve CD8+ 
                 HTR7 (Entrez: 3363)  
                 0.93  
               
               
                 Human Naïve CD4+ 
                 HTR7 (Entrez: 3363)  
                 0.56 
               
               
                   
               
            
           
         
       
     
     Example 7—Evaluation of Serotonin Secretion by T Cells 
     CD8+ T cells were isolated from human PBMCs using negative magnetic bead selection (Stemcell Technologies) and cultured in T-Cell Expansion Media (StemCell). T cells were activated with Dynabeads Human T-Activator CD3/CD28 (Invitrogen) and 30 ng/mL recombinant human IL-2 (Peprotech) or left unactivated. 
     CD8+ T cells in culture were found to produce serotonin, as detected by ELISA (Novus Biologicals). When CD8+ T cells were activated, serotonin levels dropped. Because there was no other cellular source of serotonin in the culture, it seems that CD8+ T cells actively produced and released serotonin. 
     Serotonin levels in the cultures of human CD8+ T cells that were activated or left unactivated are shown in Table 21 below. 
     
       
         
           
               
             
               
                 TABLE 21 
               
             
            
               
                   
               
               
                 SEROTONIN LEVELS  
               
               
                 IN MEDIA OF CD8+ T CELLS 
               
            
           
           
               
               
               
            
               
                   
                   
                 Average serotonin  
               
               
                   
                 Culture conditions 
                 level (nM) 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Media Only  
                 &lt;0.01 
               
               
                   
                 Unactivated CD8+ T-Cells: Donor 1  
                 0.0497 
               
               
                   
                 Activated CD8+ T-Cells: Donor 1  
                 &lt;0.01 
               
               
                   
                 Unactivated CD8+ T-Cells: Donor 2 
                 5.14 
               
               
                   
                 Activated CD8+ T-Cells: Donor 2  
                 3.24 
               
               
                   
                   
               
            
           
         
       
     
     Other Embodiments 
     While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the invention that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. Other embodiments are within the claims.