bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Endocannabinoid System: a new anti-inflammatory target in rheumatoid arthritis
Authors: TAN KYLE BOON CHIN , Murray Elaine K , Watterson Steven , Alexander Denis , Linden James , Gibson David S 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is characterised by the loss of regulatory T cell (Treg) mediated suppression of inflammatory T helper cells. RA patients with loss of immune tolerance display elevated levels of circulating pro-inflammatory cytokines. The endocannabinoid system (ES) present on immune cells may represent a novel target for development of anti-inflammatory treatments. We screened the therapeutic potential of a phytocannabinoid compound, GL1b, in an ex vivo, peripheral blood mononuclear cell (PBMC) inflammatory model. PBMCs were cultured with CD3/CD28 and IL-2 to activate and expand T cells. Inflammation was induced by phorbol 12-myristate-13-acetate (PMA)/ionomycin activation, over 4 hours. Inflamed PBMCs were treated with 0, 10, 20 and 50 μM GL1b for 24 hours, then harvested for flow cytometry analysis of Tregs. Cytokine mRNA expression and conditioned media concentration were analysed with qRT-PCR and ELISA, respectively. Results will be fed into in silico model. 50 μM GL1b significantly suppressed the total Treg population (p&lt;0.05), and relative numbers of CD69+, FOXP3+ and CTLA4+ Treg subpopulations decreased in a dose-responsive manner. A trend toward increased mean fluorescent intensity (MFI) of FOXP3 and CTLA4 was observed at 10 μM, relative to vehicle. A significant (p&lt;0.01) decrease was observed in IL-6 mRNA relative to vehicle with 50 μM GL1b, whereas at 10 – 20 μM concentrations, a trend toward lower IL-6, TNFα, IL-10 expression was evident. Conversely, secreted cytokine concentrations were increased at 10 – 20 μM GL1b, relative to vehicle. Although the phytocannabinoid GL1b reduces the overall Treg population, activated and suppressive Treg subpopulations are elevated and cytokine gene expression reduced.
In Vivo Generation of Autoantigen-specific Treg Cells in Treating Experimental Autoimmune Uveitis Without Compromising Anti-Tumor Immunity
Authors: Chen Jun , Chen Zilin , Chong Wai Po , Zhang Tian , Zhou Hongyan , Chen Wanjun 
Published: January 2023

Abstract
Generation of autoantigen-specific regulatory T (Treg) cells that suppress tissue-specific autoimmunity without compromising beneficial immune responses is the holy-grail for immunotherapy to autoimmune diseases. In a model of experimental autoimmune uveitis (EAU), we show here that we successfully generated retinal autoantigen-specific Treg cells in vivo by inducing CD4+ T cell apoptosis with antibody followed by administration of retinal autoantigen peptides (e.g., interphotoreceptor retinoid-binding protein) in mice with established EAU. We demonstrated that the therapeutic approach resulted in long-term remission of ocular inflammation and rescue of retinal function in the eyes of the mice with EAU. Mechanistically, this therapeutic effect was mediated by the generation of retinal antigen-specific Treg cells that inhibited uveitogenic Th17 response in TGF-β and IL-10 dependent manner. Importantly, these tolerized mice did not compromise their anti-tumor immunity in a model of melanoma. Thus, we have discovered a specific immunotherapy of EAU by in vivo generation of retinal antigen-specific Treg cells, which should have implication for patients with autoimmune uveitis.
Inhibition of Aurora-A recruited CD8+ T cells infiltration via mediating IL-10 production of cancer cells
Authors: Yang Jing , Han Jing , Jiang Zhen , Wang Chennan , Chen Xin , Li Rongqing , Sun Na , Liu Xiangye , Zheng Kuiyang , Ikezoe Takayuki 
Published: January 2023

Abstract
It has been shown that approximately 10% of infiltrated CD8+ T cells could be the tumor-specific intratumoral CD8+ T cells in colorectal cancer. While, inhibition of Aurora-A, a member of serine/threonine Aurora kinase family, by alisertib promoted the percentage of infiltrated intratumoral CD8+ T cells. We therefore assumed that targeting Aurora-A could be a therapeutic strategy for recruitment of intratumoral CD8+ T cells.
In CT-26 tumor model, blockade of Aurora-A with alisertib slowed the tumor growth in association with an increased infiltration, activation and expansion of intratumoral CD8+ T cells. We further analyzed the role of Aurora-A in colon cancer associated to colitis using the azoxymethane/dextran sodium sulphate (AOM/DSS) colitis-associated colon cancer model, and found that AURKA deficiency significantly decreased tumor formation, in parallel with an increase in infiltration of intratumoral CD8+ T cells. Gene expression profiling indicated that Il10ra expression was obviously increased in intratumoral CD8+ T cells sorted from alisertib-treated tumors. Antibody-mediated blockade of IL-10Ra dramatically attenuated the anti-tumor ability of alisertib in association with reducing the percentage of intratumoral CD8+ T cells. IL-10Ra was the key mediator of IL-10. We herein examined the levels of IL-10 and found that the levels of IL-10 in the serum of AURKA deficiency mice treated with AOM/DSS were elevated. Additionally, IL-10 obviously promoted migration of CD8+ T cells in vitro. Blockade of Aurora-A increased the transcriptional levels of IL-10.
In conclusion, inhibition of Aurora-A could be useful for recruiting infiltration of intratumoral CD8+ T cell by mediating IL-10 production.
CD4 Cytotoxic T cells play a critical role in anti-tumor protection
Authors: Thiault Nicolas , Husain Mushtaq , Chen Angeline , Larange Alexandre , Cheroutre Hilde 
Published: January 2023

Abstract
The CD4 T cell lineage is established in the thymus by the transcription factor, ThPOK. In the periphery, ThPOK maintains the CD4 T helper commitment and allows the differentiation to different helper fates in response to stimulation with cognate antigens. We demonstrated that in the intestine, chronic stimulation of CD4 T cells results in the loss of ThPOK expression leading to the reprogramming of the T helper cells to cytotoxic T lymphocytes (CTL), expressing notably CD8 T cells attributes. Continuous activation in a non-immunogenic environment is also a hallmark of tumor progression.
We investigated if the tumor environment supports the generation of CD4 CTL and moreover if they play essential roles in anti-tumor protection. Using the well-defined melanoma B16 model, we observed that CD4 T cells responding to the tumor uniquely lose ThPOK expression. To address the importance of the CD4 CTL in the tumor immune surveillance, we engineered two unique mouse models, in which either all the CD4 T cells are forced to reprogram to CTL or else, prevented from reprogramming to CTL. Using these models, we observed that the forced CD4 CTL eradicate melanoma cells, whereas the CD4 cells which cannot lose ThPOK and reprogram to CTL are ineffective against the tumor growth. These findings underscore the importance of CD4 CTL reprogramming in protective immunity. Finally, we developed a culture system to induce the reprograming of CD4 Th to CTL in vitro. We injected in vitro-generated CD4 CTL alone or with a co-transfer of CD8 T cells into Rag deficient hosts bearing tumor. As compared to the transfer of the CD4 CTL or CD8 CTL alone, the cooperation of the cytotoxic effector cells displayed a strong synergized effect on long term protection against tumor growth.
Response to FOLFIRINOX neoadjuvant chemotherapy is associated with a high prevalence of Tbet expressing T cells in pancreatic cancer patients
Authors: Peng Hui , James Alston , Cullinan Darren R , Mudd Jacqueline , Takchi Rony , DeNardo David G , Fields Ryan C , Goedegebuure Simon Peter , Hawkins William G 
Published: January 2023

Abstract
FOLFIRINOX is the first line treatment option for patients with pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant chemotherapy has a beneficial effect on overall survival in PDAC in comparison with upfront surgery and adjuvant therapy. However, chemotherapy has not yet been successfully combined with immune therapy in PDAC. Herein, we characterize the immunologic effect of FOLFIRINOX and thus provide a rationale for future combination with immune therapy in PDAC. Peripheral Blood Mononuclear Cells were obtained from treatment-naïve (n=20) and FOLFIRINOX-treated patients (n=15) with primary PDAC tumors. Immune cell subset composition was assessed by using mass cytometry (CyTOF). Response to FOLFIRINOX was defined as a reduction in tumor size by more than 30%. 8 of 15 patients were considered responders with a range from 32 to 60% reduction in tumor volume. Responders to FOLFIRINOX showed a significantly higher proportion of CD8+ T cells and lower proportion of monocytes in their peripheral blood compared to treatment naïve patients (both p&lt;0.05). Responders to FOLFIRINOX treatment also showed a significantly lower percentage of CD39+ Treg cells and a significantly higher percentage of CXCR3+CCR6+ Th1/Th17 cells compared to treatment naïve patients (both p&lt;0.05). Lastly, FOLFIRINOX responders showed significantly higher proportions of Tbet expressing CD4+ and CD8+ T cells compared to non-responder patients (both p&lt;0.05). Taken together, our study reveals that neoadjuvant chemotherapy with FOLFIRINOX could enhance functional T cells and down-regulate suppressor cells in circulation. Thus, combination neoadjuvant FOLFIRINOX chemotherapy with immunotherapy may improve clinical outcome.
CD40 signaling induces type I interferon and immune control in mouse pancreatic cancer lacking the CXCL12-coat
Authors: Li Jiayun , Wang Zhikai , Fearon Douglas T 
Published: January 2023

Abstract
Pancreatic ductal adenocarcinoma (PDA) has a low 5 year survival rate of 8.5% because of its late diagnosis and resistance to the existing therapies. Patients with PDA who are microsatellite stable do not respond to check point blockade immunotherapy due to impaired T cell infiltration, which is mediated by the CXCL12-coat on cancer cells (Wang Z, et al. bioRχiv). In mouse hepatic metastases established with PDA cells from the KPC model of PDA, Krt19-CRISPR/Cas9-edited tumors lacking the CXCL12-coat showed a type I interferon (IFN) response as well as T cell infiltration and activation compared to the control scramble tumors. By RNA FISH, we found that IFNb1 is dominantly produced by CD40+ cells, and not by SiglecH+ plasmacytoid dendritic cells. RNA sequencing data showed up-regulation of Cd40lg in the Krt19-edited tumors compared to the scramble tumors. Administration of antagonistic anti-CD40 antibody prior cancer cells inoculation abolished IFNb1 production, T cell accumulation and activation. To confirm the role of CD40, administration of agonistic anti-CD40 antibody to mice bearing wild type PDA tumors elicited intra-tumoral IFNb1 production in CD11b+ CD11c+ myeloid cells. The T cell infiltration and activation induced by agonistic anti-CD40 antibody treatment sensitized both subcutaneous pancreatic tumors and hepatic metastases to anti-PD1 treatment. These findings indicate that the expression of CD40L elicits an intra-tumoral type I IFN response that is required for immune control of PDA tumors in which CXCR4 signaling is impaired.
Promoting antitumor immunity and increased T-cell function by depletion and blockade of the immunosuppressive cell compartment in murine cancer
Authors: Smith Timothy M , Camarena Carmen , Bear Harry , Martin Rebecca 
Published: January 2023

Abstract
Tumor growth occurs due to a failure of the immune system to recognize and destroy malignant cells. The cause of breakdown in immune surveillance is at the systemic level and at in the tumor microenvironment. These changes can even occur in the tumor cells themselves to make them less detectable by anticancer immune cells such as downregulation of tumor-associated antigens or decreased expression of antigen presenting molecules such as MHCI. In addition, many cancer types will upregulate immune checkpoint molecules, such as PD-L1 which binds to PD-1 on cytotoxic T-cells to suppress antitumor immune cell function. Immune surveillance can also be curtailed by the presence of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and T-regulatory cells (T-regs) which both serve to dampen antitumor immunity. Our lab utilizes a metronomic low-dose therapeutic approach to examine the effects of anticancer drugs against murine breast cancer and the effects on the immunosuppressive cell compartments. Recent data has shown a reduction in T-regs following treatment with cyclophosphamide, a common chemotherapy. We have also shown that guadecitabine, a second-generation DNA methyl-transferase inhibitor, depletes MDSCs. Here we show that combining low-dose metronomic treatments of guadecitabine and cyclophosphamide leads to a depletion in splenic and tumor MDSCs and T-regs, increased CD8+ T-cell function in the tumor, as well as a reduction in tumor size in FoxP3 reporter mice bearing triple-negative 4T1 tumors. In addition, preliminary studies suggest this antitumor effect is amplified by combining guadecitabine and cyclophosphamide with checkpoint inhibitors such as anti-PD-1, in vivo.
A new Natural Killer cell therapy to target relapse Acute Lymphoblastic Leukemia
Authors: Vicioso Yorleny M , Beck Rose , Gram Herman , Zhang Keman , Asthana Abhishek , Wong Derek , Letterio John , Parameswaran Reshmi 
Published: January 2023

Abstract
Acute Lymphoblastic Leukemia (ALL) is the most common childhood cancer. Drug resistance and relapse are two major problems in ALL. Pre-B ALL cells express B-cell activating factor receptor (BAFF-R) on their surface, which is not present on normal pre-B cells. This makes it an attractive therapeutic target for ALL. We used a BAFF-R antibody optimized for antibody dependent cell cytotoxicity (ADCC) to enhance NK cell mediated killing of drug resistant and relapsed ALL cells, which are difficult to treat by conventional chemotherapy. We found that anti-BAFF-R antibody enhanced NK cell mediated killing of drug resistant ALL cells in vitro. Early treatment with anti-BAFF-R antibody and NK cells significantly reduced disease burden in xenograft ALL models and increased overall mice survival. However, in advanced disease, the efficacy of NK cells to mediate ADCC is reduced. ALL cells are known to produce TGF beta, a cytokine that causes NK cell dysfunction. We found that ALL cells produce TGF-β and co-culturing ALL cells with NK cells lead to a decrease in CD16 expression on NK cells, which is reversible by addition of EW-7197, a potent TGF-beta receptor I inhibitor. We found that EW-7197 treatment improved anti-BAFF-R antibody mediated ADCC of drug resistant ALL cells, in vivo, even if treatment is started late. Our data validate this novel BAFF-R antibody as a very promising tool for pre-B ALL therapy.
Combination of TEW-7197 and adoptively transferred NK cells leads to Improved Antitumor Responses in vivo
Authors: Kim Jungwon , Lim Seon Ah , Kim Tae-Jin , Lim Siyoung , Kim Jiyoung , Kim Jeongsoo , Kim Junghee , Lee Eunju , Park Sunghee , Kim Seong-Jin , Lee Kyung-mi 
Published: January 2023

Abstract
Transforming growth factor beta (TGF-β) supports tumor cell proliferation, metastasis, and invasion in later stages of cancer while suppresses the proliferation and survival of lymphocytes including Natural Killer (NK) cells. The current therapeutic approaches of targeting TGF-β include inhibiting its transcription through anti-sense oligonucleotides, blocking TGF-β receptor binding through the use of antibodies, or suppressing the TGF-beta signaling pathways using small molecules, such as TEW-7197. Here, we report the anti-tumorigenic role of TEW-7197, an orally administered TGF-b receptor kinase ALK5 inhibitor, by synergizing with adoptively transferred NK cells in the human xenograft A375 melanoma model. Addition of TEW-7197, at its therapeutic doses, in cultures of A375 melanoma cells did affect neither the growth nor the apoptotic killing of tumor cells in vitro, however, it caused reduction of tumor cell growth in vivo. This was possibly due to the upregulation of TGF-b mRNA upon tumor implantation in the xenograft tissues, which became a target of TEW-7197. Adoptive transfer of ex-vivo expanded human NK cells into these mice also inhibited tumor growth but co-administration of TEW-7197 resulted in significantly higher degree of tumor regression, by both inhibiting TGFb signaling as well as increasing the NK cell’s availability within tumor tissues. These data highlight that the anti-tumor response exhibited by TEW-7197 and NK cells are distinct, and can be synergized by the combination of the two. Therefore, our data provide the scientific rationale for the combination therapies of TGF-b small molecule kinase inhibitors with adoptively transferred NK cells in advanced cancer patients.
Immune microenvironments of early onset vs late onset colorectal cancers
Authors: Anand Sudarshan , Gardner Ivy , Siddarthan Raga , Watson Kate , Ruhl Rebecca , Tsikitis Liana V 
Published: January 2023

Abstract
Over the past 40 years, the incidence of rectal cancer in patients 20–39 years old has quadrupled. The immune microenvironment in colorectal cancer is a key player in disease progression, therapy response, and overall survival. However, the role of the immune microenvironment in early onset rectal cancer (less than 50 years old) has not been elucidated. We profiled the immune microenvironments of a cohort of early onset vs late onset (over 65 years) colorectal cancers from FFPE surgical specimens and biopsies from patients. We compared our dataset to a publicly available database (GSE8721) of gene expression profiles for 203 rectal cancer and 160 matched normal mucosa samples. We identified genes that were differentially expressed between early and late onset rectal cancer groups and validated our results with qPCR. Interestingly, we noted differences in immune signatures depending on the anatomical site (colon vs rectum). Two genes, FLT3 and SAA1, were found to have increased expression in both our patient samples and the GSE8721 rectal cancer database. FLT3 codes for fms-like tyrosine kinase receptor and activating mutations of this gene are present in 30% of acute myeloid leukemia cases and is associated with a worse prognosis. SAA1 codes serum amyloid A1 which is an acute phase protein that is highly expressed in response to inflammation. While FLT3 inhibitors did not directly affect tumor cell proliferation and cell death in vitro, we observed a decrease in tumor burden in vivo. Our data indicates that there are distinct changes in the immune microenvironment between early and late onset rectal cancer. We propose that understanding these changes will enable the development of age dependent immune modulation for this disease.
Tumor intrinsic mechanisms of immunosuppression in CD8 T cell function and response to lung cancer
Authors: Melese Etienne Sylvain , Franks Sarah Elizabeth , Cederberg Rachel , Seo Jung Hee , Lam Wan , Bennewith Kevin L , Lockwood William , Abraham Ninan 
Published: January 2023

Abstract
Immunotherapies are effective in a subset of patients with non-small cell lung cancer (NSCLC), however the majority do not respond which highlights the ongoing need for novel therapeutics and biomarkers. Tumor cells can produce cytokines and chemokines that influence both the recruitment and function of immune cells. In patients with NSCLC, the microRNA-17~92 (miR-17~92) cluster was shown to be upregulated, and high levels of microRNA-17 in serum was associated with decreased survival. We aimed to identify whether tumor cell intrinsic mechanisms, like upregulation of miR-17~92, regulate chemokine or cytokine production to induce an immunosuppressive tumor microenvironment and inhibit CD8+ T cell anti-tumor function in the lung. We used the CIBERSORTX program to evaluate alterations to immune cell populations and survival in NSCLC patients with increased chemokine or miR-17~92 expression. We found high expression of miR-17 and low expression of IL-7Rα correlated with decreased survival in lung adenocarcinoma (LAC) patients. Furthermore, LAC patient’s tumor biopsies with high miR-17 had decreased IL-7Rα and increased populations of CD8+ T cells by CIBERSORTX. We will use in vitro and in vivo models of lung cancer to determine whether miR-17~92 upregulation and tumor cell chemokines and cytokines production drives immunosuppression in the tumor microenvironment. Understanding how lung tumor cells regulate cytokines and chemokines, and their putative control of exhaustion in CD8 T cells in the tumor microenvironment would guide selection of efficacious immunotherapy treatment.
The Development, Function, and Plasticity of the Immune Macroenvironment in Cancer
Authors: Allen Breanna M , Hiam Kamir , Burnett Cassandra E , Venida Anthony , DeBarge Rachel , Carmi Yaron , Spitzer Matthew H 
Published: January 2023

Abstract
Harnessing immune defense mechanisms has revolutionized cancer therapy, but our understanding of the factors governing immune responses in cancer remains incomplete, limiting patient benefit. Here, we use mass cytometry to define the organism-wide immune landscape in response to tumor development across five tissues in eight tumor models. Systemic immunity was dramatically altered across mouse models and cancer patients, with changes in peripheral tissues differing from those in the tumor microenvironment and taking place in phases during tumor growth. This tumor-experienced immune system mounted dampened responses to orthogonal challenges, including reduced T cell activation during viral or bacterial infection. Disruptions in T cell responses were not cell-intrinsic but rather due to reduced responses in antigen-presenting cells (APCs). Promoting APC activation was sufficient to restore T cell responses to orthogonal infection. All systemic immune changes were reversed with surgical tumor resection, revealing remarkable plasticity in the systemic immune state, which contrasts with terminal immune dysfunction in the tumor microenvironment. These results demonstrate that tumor development dynamically reshapes the composition and function of the immune macroenvironment.
Reprogramming the tumor microenvironment with next-generation chaperone-based immunolytic agent for cancer immunotherapy
Authors: Guo Chunqing , Liu Wenjie , Yu Xiaofei , Subjeck John R. , Repasky Elizabeth A , Wang Xiang-Yang Shawn 
Published: January 2023

Abstract
The tumor microenvironment (TME) represents a major barrier for successful cancer immunotherapy due to tumor-associated immunosuppressive pathways that facilitate immune evasion and therapeutic resistance. We recently created a multifunctional chimeric chaperone (i.e., Flagrp170) by incorporating the flagellin-derived NF-κB-stimulating sequence for superior antigen cross-presentation and co-stimulation. Upon intralesional administration, this immunolytic agent results in profound inhibition of multiple mouse tumors including melanoma, prostate cancer, colorectal cancer, and mammary tumor. Strikingly, reprogramming the TME with Flagrp170 induces elevation of multiple Th1 cytokines such as GM-CSF, IL-12 and IFN-γ. Mechanistic studies reveal that GM-CSF is mainly produced by CD8+ T cells and is indispensable for the antitumor efficacy of in situ Flagrp170 therapy. Neutralizing GM-CSF abrogates the antitumor activity of the Flagrp170, which is associated with reduced mobilization and recruitment of dendritic cells (DCs) as well as IFN-γ-expressing T cells, suggesting that GM-CSF-derived from tumor-infiltrating T cells is essential for expansion and/or function of DCs within the TME. Our findings elucidate an immunological mechanism of action of the Flagrp170 in skewing the TME towards a Th1-polarized immunostimulatory phenotype and provide a novel approach to reprogramming the immune landscape of the TME for improved immunotherapeutic outcomes.