bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B119: Characterization of a phosphatidylserine, TAM receptor (Tyro3, Axl, Mertk), PDL1 axis in breast cancer
Authors: Kasikara Canan , Kumar Sushil , Geng Ke , Davre Viral , Empig Cyril , Freimark Bruce , Gray Michael , Schlunegger Kyle , Hutchins Jeff , Kotenko Sergei V. , Birge Raymond B. 
Published: November 2016

Abstract
Tyro3, Axl and Mer (TAMs) are three homologous receptor tyrosine kinases that bind vitamin K-dependent endogenous ligands, Protein S (PROS1) and Gas6, and act as bridging molecules to promote PS-mediated clearance of apoptotic cells (efferocytosis). In recent years, evidence has accumulated that TAMs are overexpressed in a wide array of tumor types, whereby the level of expression correlates with the tumor grade and the emergence of chemo and radio resistance to targeted therapeutics. TAMs have also been implicated as inhibitory receptors on myeloid-derived cells that suppress anti-tumor immunity. In addition to TAM overexpression, externalized PS is also concomitantly up-regulated in the tumor microenvironment, suggesting that PS and PS receptors might act as immune checkpoint inhibitors. To better understand the biology of TAMs, and the specificity of interaction between TAMs and PS, we generated chimeric TAM reporter cell lines comprised of the extracellular domains of each TAM fused to the intracellular domains of the IFNR1, as well as cell lines stably expressing full-length native TAMs. Using these systems, we found that each TAM receptor has a unique pattern of activation by GAS6 and PROS1, as well as unique dependency for PS on apoptotic cells, PS liposomes, and exosomes. Interrogating epithelial cells that express WT TAMs, we also observed that each TAM showed differential capacity for efferocytosis, AKT-mediated chemo-resistance, and their ability to up-regulate the immune checkpoint inhibitory ligand PD-L1 on breast cancer cells. Functionally, TAM-mediated efferocytosis and PD-L1 up-regulation could be partially blocked by PS targeted antibodies 11.31 and bavituximab, suggesting the existence of a PS/PS-R (TAM-receptor)/PD-L1 axis that drives immune escape in solid cancers. These studies demonstrate that, despite their similarities, Tyro3, Axl and Mertk are likely to perform distinct functions in both immune-regulation and the recognition and removal of apoptotic cells. Finally, these studies provide a rationale for combinatorial therapeutics targeting PS, TAM, and PD-L1 as immune checkpoint inhibitors in the treatment of cancer.
Citation Format: Canan Kasikara, Sushil Kumar, Ke Geng, Viral Davre, Cyril Empig, Bruce Freimark, Michael Gray, Kyle Schlunegger, Jeff Hutchins, Sergei V. Kotenko, Raymond B. Birge. Characterization of a phosphatidylserine, TAM receptor (Tyro3, Axl, Mertk), PDL1 axis in breast cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B119.
Abstract B131: Quantitative modeling of Syk regulation in B cell chronic lymphocytic leukemia
Authors: Frushicheva Maria P. 
Published: November 2016

Abstract
Spleen tyrosine kinases (Syk) are initiators of B cell receptor-mediated (BCR) signaling events, enabling cells to drive chronic lymphocytic leukemia (CLL) progression. However, the mechanistic principles of biochemical signaling pathways that contribute to CLL pathogenesis are poorly understood. This study investigates Syk-mediated molecular pathways of the BCR signaling network using computational modeling. An expression of ζ chain-associated protein kinase of 70 kD (ZAP-70, Syk-family protein kinase) in the BCR signaling pathway is an adverse prognostic marker in CLL. Therefore, we need a better understanding of molecular mechanisms of Syk family protein kinases and effects of their inhibitors in the BCR signaling pathway. In this work, we dissected several computational models of ZAP-70 and SYK regulation to design an integrated mechanistic description of the BCR signaling pathway, and to explain the observed differences in the clinical behaviors of ZAP-70+ / ZAP-70- phenotypes of CLL patients. Specifically, we characterized the effects of different ZAP-70 and SYK expression and phosphorylation levels on the BCR activation threshold, using stochastic simulations of the BCR signaling network. Preliminary findings suggest that ZAP-70 serves as an adaptor protein that facilitates the recruitment of SYK to the BCR complex. We find that the expression of ZAP-70 enhances the BCR signaling, and therefore correlates with a more aggressive disease course. Our results will help in the development of novel therapies targeting Syk functions to regulate B-CLL responses.
Citation Format: Maria P. Frushicheva. Quantitative modeling of Syk regulation in B cell chronic lymphocytic leukemia [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B131.
Abstract B143: Fc gamma receptor IV mediated depletionof tumor infiltrating regulatory T cells by anti-CTLA4 antibody is promoted byTLR1/2 agonist and hence its efficacy in anti-tumor combination therapy
Authors: Sharma Naveen , Allison James P. 
Published: November 2016

Abstract
Immune checkpoint blockade therapy has been effective but still a significant number of cancer patients either do not respond or become resistant to these therapies. We hypothesized that activating innate immune pathway along with adaptive immune pathway will have a better tumor reduction and survival outcome from immunotherapy treatment. Therefore, we injected TLR1/2 ligand intratumorally in combination with intraperitoneal injection of anti-CTLA4 antibody in a mouse model of melanoma. We show that this combination treatment enhanced anti-tumor immune responses both qualitatively and quantitatively, which is dependent on both CD4 and CD8 T cells. Interestingly, Our results further suggested that increased depletion of regulatory T cells in tumor microenvironment could be one of the mechanisms of enhanced efficacy of combination therapy and this efficacy is dependent upon Fcγ receptor IV expression. This study shows modulation of Fcγ receptor IV expression by a TLR ligand on macrophages to be important in efficacy of anti-CTLA4 antibody in a combination therapy and this mechanism could be harnessed to modulate the final outcome of other antibody-based immunomodulatory therapies.
Citation Format: Naveen Sharma, James P. Allison. Fc gamma receptor IV mediated depletionof tumor infiltrating regulatory T cells by anti-CTLA4 antibody is promoted byTLR1/2 agonist and hence its efficacy in anti-tumor combination therapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B143.
Abstract B145: Small molecule inhibition of cyclic GMP-AMP synthase reduces interferon expression in macrophages from an autoimmune mouse model
Authors: Gao Pu 
Published: November 2016

Abstract
Cyclic GMP-AMP synthase (cGAS) plays a central role in sensing aberrantly localized cytoplasmic dsDNA. Upon binding dsDNA, cGAS synthesizes the cyclic dinucleotide cGAMP, which acts as a second messenger to initiate a signaling pathway for the induction of interferon genes. Given that cytoplasmic DNA can originate from bacteria or virus, cGAS is essential for innate immunity against pathogenic infection. Conversely, cGAS detection of mislocalized nuclear or mitochondrial DNA can lead to hyper-inflammation. Recent studies indicate that cGAS can potentiate autoimmunity in cases of lupus, Aicardi-Goutières syndrome, and other related diseases—suggesting that targeting cGAS activity may be therapeutically beneficial. We report the discovery of a first-in-class generation of cGAS small molecule inhibitor, RU.365, identified in a high-throughput screen. Its structure-activity relationship, and selectivity and potency in cellular assays, was characterized. Moreover, we solved the structure of cGAS in complex with dsDNA and RU.365 or its close structural analog within the active site. Finally, we demonstrate that the inhibitor can reduce constitutive expression of interferonin macrophages derived from a mouse model of autoimmunity. RU.365 will be useful towards understanding the biological roles of cGAS and can serve as a molecular scaffold for development of future autoimmune therapies.
Note: This abstract was not presented at the conference.
Citation Format: Pu Gao. Small molecule inhibition of cyclic GMP-AMP synthase reduces interferon expression in macrophages from an autoimmune mouse model [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B145.
Abstract IA07: Antitumor T cells: You are what you eat
Authors: Cui Guoliang , Ho Ping-Chih , Amezquita Robert , Kaech Susan 
Published: November 2016

Abstract
Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. In contrast, resting memory CD8 T cells depend less on high rates of glycolysis and more on fatty acid oxidation to persist, self-renew, and respond to secondary infection. This talk will discuss the concept of metabolic checkpoints for immune cells in tumors, referring to the idea that the nutrients utilized by different types of T cells can affect both their energetic demands and their functionality. In particular, the metabolic state of exhausted T cells found in tumors has only recently been studied. Our data in mouse models of cancer suggest that a glucose-poor, fatty acid-rich tumor microenvironment limits aerobic glycolysis, but promotes fatty acid uptake in tumor-infiltrating T cells, which suppresses tumoricidal effector functions and increases PD-1 expression. This talk will discuss recent analyses of the signaling pathways that respond to these nutrient alterations in T cells in tumors and how this may relate to new modalities of treatment in combination with checkpoint blockade.
Citation Format: Guoliang Cui, Ping-Chih Ho, Robert Amezquita, Susan Kaech. Antitumor T cells: You are what you eat [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA07.
Abstract IA08: Identifying and overcoming metabolic checkpoints to antitumor immunity
Authors: Delgoffe Greg M. 
Published: November 2016

Abstract
It has now become clear that the immune system is not oblivious to cancer initiation and progression, but rather is rendered dysfunctional through a wide array of tolerogenic mechanisms. One of these is the generation of a potently immunosuppressive microenvironment, characterized by altered populations of suppressive cells, secretion of suppressive cytokines, and upregulation of inhibitory ligands. The tumor microenvironment also possesses, due to the deregulated energetics of cancer cells, an altered metabolic profile: hypoxia, acidosis, and a dearth of glucose and other carbon sources. T cell activation and effector function are metabolically demanding, requiring elevated glucose processing and mitochondrial activity to keep up with the bioenergetic demands of proliferation, cytokine secretion, and cytolytic capacity. Thus, we sought to determine whether the metabolism of the tumor microenvironment acts as a barrier to antitumor immunity and resistance mechanism to immunotherapy. We have demonstrated that T cells infiltrating murine and human tumors exhibit a phenotype of metabolic insufficiency, characterized by decreased glucose uptake and a crippling loss of mitochondrial function. We show that this loss of oxidative function is specific to the chronic activation observed in the tumor microenvironment, and occurs rapidly upon entry into the tumor. This loss of mitochondrial activity and mass is due, in part, to the repression of PGC1α, a transcriptional co-activator that programs mitochondrial biogenesis. Further, we have identified chronic Akt activation and consequent Foxo inactivation as a major driver of PGC1α repression. Importantly, metabolic reprogramming of tumor-specific T cells to enforce mitochondrial biogenesis results in dramatically increased antitumor immunity, characterized by robust proliferation, cytokine production, and tumor regression and clearance. Our data support a model in which mitochondrial insufficiency represents a primordial checkpoint inhibiting antitumor immunity in addition to immunologic suppression. Further supporting this notion are additional studies from our laboratory suggesting that selective boosting of T cell mitochondrial activity through mitigation of tumor hypoxia dramatically enhances immunotherapies like checkpoint blockade and adoptive cell therapy. Our data suggest not only that the metabolic nature of the tumor microenvironment may be predictive of a patient's response to various immunotherapies, but that metabolic reprogramming of T cells or the microenvironment itself may be an important means to improve the immunotherapeutic treatment of cancer.
Citation Format: Greg M. Delgoffe. Identifying and overcoming metabolic checkpoints to antitumor immunity [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA08.
Abstract IA13: Immune suppressive and immune stimulating monocytes in cancer
Authors: Bronte Vincenzo 
Published: November 2016

Abstract
The tumor environment is enriched in myeloid cells, which can either promote or fight tumor progression. By releasing soluble mediators—such as cytokines, interleukins, metabolites, and growth factors—tumors stimulate a reactive myelopoiesis at both medullary and extra-medullary sites such as the spleen, which alters the steady-state myeloid differentiation, pushing proliferation and expansion of myeloid elements that acquire immunosuppressive and pro-tumoral functions. This process is regulated by the fine balance between pro-survival and anti-apoptotic programs in myeloid cells. The frequency and the function of myeloid-derived suppressor cells (MDSC) in the blood of tumor patients is now regarded as a negative prognostic marker, which correlates with the clinical outcome and response to therapy, including both conventional chemotherapy as well as immunotherapy. Recent data suggest that the monocytic compartment within MDSC (M-MDSC) in tumor-conditioned hosts is extremely plastic. Different pathways activated in M-MDSC, including the metabolism of the semi essential amino acid L-arginine, exert a negative influence on the proliferation and functions of antigen-stimulated T lymphocytes. In fact, the inability of T lymphocytes to recognize and destroy tumor cells can depend on the suppressive milieu shaped by the two enzymes involved in L-arginine metabolism. On the other hand, nitric oxide-producing cells derived from monocytes can support cancer cell destruction and tumor regression. In fact, even though tumor-specific CD8+ T cells are negatively influenced by intra-tumoral L-arginine metabolism, they can license a subset of monocytes to aid tumor rejection, which depends on increased tumor antigen presentation and nitric oxide synthase 2 induction, as the result of the intratumor activation of the CD40-CD40L axis. Understanding the molecular events and cell biology of immune stimulating and immune suppressive monocytes can provide additional targets to modify the tumor environment and enhance cancer immunotherapy.
Citation Format: Vincenzo Bronte. Immune suppressive and immune stimulating monocytes in cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA13.
Abstract IA27: Novel natural killer cell targets for cancer immunotherapy
Authors: Smyth Mark J. , Putz Eva , Blake Stephen , Gao Aaron , Guimaraes Fernando , Miles John , Dougall Bill , Teng Michele WL , Huntington Nicholas D. 
Published: November 2016

Abstract
Avoiding immune destruction is a hallmark of cancer. Natural killer (NK) cells contribute to tumor immune surveillance and protection from tumor metastasis. The cell surface Ig superfamily molecule CD96 has recently been shown as a negative regulator of mouse NK cell activity, and we have demonstrated that blocking CD96 with a monoclonal antibody inhibited experimental metastases in multiple tumor models. The anti-metastatic activity of anti-CD96 was dependent on NK cells, CD226 (DNAM-1) and IFN-γ, but independent of activating Fc receptors. Anti-CD96 was more effective in combination with anti-CTLA4, anti-PD1, anti-TIGIT, or doxorubicin chemotherapy. Development of additional anti-mouse and anti-human CD96 mAbs will be discussed. Overall these data demonstrate that blocking CD96 is a new and complementary immunotherapeutic strategy to reduce tumor metastases. The activity of NK cells is also governed by the cytokine IL-15, foreign and self-ligands, and a variety of immunosuppressive factors. We have identified CIS (Cytokine-inducible SH2-containing protein; Cish gene) as the critical negative regulator of IL-15 signalling in NK cells and shown the critical intrinsic role of CIS in suppressing NK cell control of tumor initiation and metastasis. The combination of Cish-deficiency and relevant immunotherapies, such as immune checkpoint blockade antibodies, IL-2, and type I interferon revealed further improved control of metastasis. The data clearly indicates that targeting CIS promotes NK cell antitumor functions and CIS holds great promise as a novel target in NK cell immunotherapy. The relative importance of mechanisms that tumors adopt to evade NK cells remains ill defined. Using mice with NK cells that either constitutively, or are unable to, signal via the TGF-β receptor, revealed that TGF-β signaling induces the transdifferentiation of conventional NK (cNK) cells into ILC1. Functional analysis revealed that host protection from tumor initiation and metastasis is mediated by cNK cells, whereas tumor resident ILC1 and ILC1-like cells appear to offer no host protection. These data indicate the plasticity of cNK cells under pathophysiological conditions and a potential new escape mechanism for tumors from innate immunity.
Citation Format: Mark J. Smyth, Eva Putz, Stephen Blake, Aaron Gao, Fernando Guimaraes, John Miles, Bill Dougall, Michele WL Teng, Nicholas D. Huntington. Novel natural killer cell targets for cancer immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA27.
Abstract IA29: Manipulating inflammation to raise cancer immunogenicity
Authors: Zelenay Santiago 
Published: November 2016

Abstract
Cyclooxygenase (COX)-2, one of the rate-limiting enzymes for production of prostanoids, is commonly upregulated in numerous cancers, and together with prostaglandin E2 (PGE2), has been implicated in several aspects of malignant growth including proliferation, angiogenesis, and invasion. We found that COX-dependent production of PGE2 by melanoma cells dominantly and primarily enables progressive tumor growth via immune escape. Melanoma cells, unable to produce PGE2 by means of genetic ablation of COX or prostaglandin E synthase, formed spontaneously regressing tumors in immune-competent mice but progressive tumors in immune-deficient hosts. By contrast, their PGE2-competent parental lines grew progressively and irrespectively of the presence of a fully competent immune system, demonstrating an essential role for PGE2 in immune evasion. Importantly, PGE2-dependent immune escape was crucial not only in melanoma but also in colorectal and breast cancer models, arguing that this is a general mechanism for subversion of anticancer immunity. COX deficiency in cancer cells was associated with a marked shift in the inflammatory signature at the tumor site characterized by lower expression of cancer-promoting factors and concomitant increase in several mediators typically associated with antitumor immunity. These drastic changes in the inflammatory nature of the tumor microenvironment due to reduced PGE2 levels suggested that COX inhibitors could be used to potentiate immune-dependent control. Indeed, we found that combining COX-inhibitors, such as aspirin, with anti-PD-1 blockade synergistically promoted growth control of tumors poorly responsive to either monotherapy. Finally, analysis of publicly available human melanoma datasets revealed a remarkable conservation of the COX-driven mouse inflammatory signature suggesting that COX activity might be a driver of immune suppression across species.
Citation Format: Santiago Zelenay. Manipulating inflammation to raise cancer immunogenicity [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA29.