bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A116: Lipid control of DNA-stimulated innate immunity
Authors: Tan Xiaojun , Zhang Conggang , Chen Zhijian J. 
Published: February 2019

Abstract
Type I interferon (IFN) plays essential roles in both spontaneous and iatrogenic tumor immunogenicity. Tumor-derived DNA is recognized by 2’,3’-cyclic GMP-AMP (cGAMP) synthase (cGAS) that is important in tumor immunogenicity. Upon DNA binding, cGAS produces the endogenous second messenger cGAMP that binds to and activates stimulator of IFN genes (STING), a signaling adaptor. cGAMP binding triggers STING trafficking from the endoplasmic reticulum (ER) to perinuclear compartments, with simultaneous activation of serine/threonine-protein kinase TBK1 that in turn phosphorylates the transcription factor IRF3, leading to upregulation of type I interferons. However, where and how TBK1 is activated by STING upon cGAMP stimulation is unclear. Our study focuses on the regulation of cGAMP-stimulated STING trafficking and activation by lipid messengers with essential roles in subcellular protein/membrane trafficking and signaling. Through in vitro signaling reconstitution, we identified a cellular lipid as an essential factor of STING signaling. We found both STING and TBK1 were lipid effectors. Lipid binding not only promotes STING trafficking but also stimulates TBK1 activation. These results reveal a new component of the STING-TBK1 complex that controls cytosolic DNA-stimulated innate immune signaling.
Citation Format: Xiaojun Tan, Conggang Zhang, Zhijian J. Chen. Lipid control of DNA-stimulated innate immunity [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A116.
Abstract A125: Pulsatile MEK inhibition improves antitumor immunity and T-cell function in Kras mutant lung cancer
Authors: Choi Hyejin , Deng Jiehui , Li Shuai , Silk Tarik , Brea Elliott J. , Boiarsky Jonathan , Akbay Esra A. , Smith Paul D. , Merghoub Taha D. , Wong Kwok-Kin , Wolchok Jedd D. 
Published: February 2019

Abstract
KRAS is one of the most commonly identified driver oncogene in non-small cell lung cancer (NSCLC) and is commonly associated to NSCLC that is refractory to current available modalities of treatment. Targeted therapy to inhibit MEK has shown promising tumor growth control, but is followed by quick rebound of tumor growth. Recently, cancer immunotherapy has shown great promise by activating T-cells that are suppressed in the tumor microenvironment, especially through targeting co-inhibitory molecules and their counterparts. We sought to identify the most effective therapy for the treatment of KRAS mutant NSCLC patients by targeting cancer cells and activating immune infiltrates at the same time, by studying the impact of MEK inhibition on the immune microenvironment. We utilized Kras mutant lung cancer cell lines and Kras mutant transgenic lung cancer animals. We found that pulsatile treatment of MEK inhibitors activates T-cells and releases their proliferation suppression ex vivo and in vivo. Both selumetinib and trametinib showed highly increased CTLA-4 expression and mild increase of PD-1 in T-cells in pulsatile treatment, compared to continuous treatment in vivo. In addition, the pulsatile schedule alone showed superior antitumor effect and delayed drug resistance, in contrast with continuous dosing schedule. Based on the above observations, we combined pulsatile MEK inhibitor treatment and anti-CTLA-4 and found that it showed most prolonged survival of Kras tumor-bearing mice. All together, our findings will set the foundation for a combinatorial therapeutic strategy using pulsatile targeted therapy together with immunotherapy in patients, to optimally enhance tumor apoptosis and promote long-term immune response simultaneously.
Citation Format: Hyejin Choi, Jiehui Deng, Shuai Li, Tarik Silk, Elliott J. Brea, Jonathan Boiarsky, Esra A. Akbay, Paul D. Smith, Taha D. Merghoub, Kwok-Kin Wong, Jedd D. Wolchok. Pulsatile MEK inhibition improves antitumor immunity and T-cell function in Kras mutant lung cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A125.
Abstract A159: Agonistic CD40 antibody therapy induces formation of tertiary lymphoid structures in glioma and inhibits the response to immune-checkpoint blockade
Authors: Hooren Luuk van , Vaccaro Alessandra , Georganaki Maria , Ramachandran Mohanraj , Huang Hua , Lau Joey , Smits Anja , Essand Magnus , Dimberg Anna 
Published: February 2019

Abstract
Cancer immunotherapy of glioma, the most common primary brain tumor in adults, is constrained by an immunosuppressive microenvironment. Tertiary lymphoid structures (TLSs) are ectopic lymphoid structures that mediate immune responses and provide a local site for tumor antigen presentation. Here, we show for the first time that TLSs are present in human low-grade glioma and that they can be induced in murine glioma models. Agonistic CD40 antibodies induced lymphotoxin α expression in B cells and enhanced the formation of TLSs in mice bearing orthotopic GL261 or CT-2A gliomas. TLSs consisting of B cells, T-cells and antigen presenting cells formed around CD31+ vessels proximal to the tumor tissue and adjacent to the meninges. Agonistic CD40 antibody treatment improved the CD8+ T-cell / Treg ratio in tumor-bearing mice, but there was no survival benefit. A decreased CD69 activation status on CD8+ T-cells, an increase of B cells with a CD1d+CD5+ regulatory phenotype and a high infiltration of Tregs in TLSs indicate that agonistic CD40 antibodies induce an immunosuppressive microenvironment in glioma. Consistent with this, the efficacy of both PD-1 and CTLA-4 checkpoint blockade was significantly decreased by co-administration of agonistic CD40 antibodies. These results demonstrate that TLSs are present and can be induced in glioma, but that they at least under certain conditions are associated with immunosuppression, shedding light on new mechanisms of immune regulation in the brain microenvironment.
Citation Format: Luuk van Hooren, Alessandra Vaccaro, Maria Georganaki, Mohanraj Ramachandran, Hua Huang, Joey Lau, Anja Smits, Magnus Essand, Anna Dimberg. Agonistic CD40 antibody therapy induces formation of tertiary lymphoid structures in glioma and inhibits the response to immune-checkpoint blockade [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A159.
Abstract A175: Memory T-cells targeting unique and shared oncogenic mutations detected in peripheral blood of epithelial cancer patients
Authors: Cafri Gal , Yossef Rami , Pasetto Anna , Deniger Drew , Gartner Jared J. , Prickett Todd , Robbins Paul F. , Rosenberg Steven A. 
Published: February 2019

Abstract
T-cells targeting shared oncogenic mutations can induce durable tumor regression in epithelial cancer patients. These T-cells can be detected in tumor-infiltrating lymphocytes, but whether such cells can be detected in the peripheral blood of patients with common metastatic epithelial cancer is unknown. Using a highly sensitive in vitro stimulation and enrichment of peripheral memory T-cells from six metastatic cancer patients, we identified and isolated memory T-cells targeting the mutated KRASG12D and KRASG12V variants, in three patients. In an additional two metastatic colon cancer patients, we detected CD8+ neoantigen-specific cells targeting the unique mutated SMAD5 and MUC4 proteins. Therefore, memory T-cells targeting KRAS and neoantigens can be detected in the peripheral blood of epithelial cancer patients and can potentially be used for the development of effective personalized T-cell-based cancer immunotherapy across multiple patients.
Citation Format: Gal Cafri, Rami Yossef, Anna Pasetto, Drew Deniger, Jared J. Gartner, Todd Prickett, Paul F. Robbins, Steven A. Rosenberg. Memory T-cells targeting unique and shared oncogenic mutations detected in peripheral blood of epithelial cancer patients [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A175.
Abstract A186: A new strategy to identify and expand tumor-reactive CD8 TILs in human solid tumors
Authors: Duhen Thomas , Duhen Rebekka , Montler Ryan , Moudgil Tarsem , Bulk Jitske van den , Fox Bernard A. , Chang Shu-Ching , Grunkemeier Gary , Verdegaal Els M.E. , Miranda Noel F. de , Leidner Rom , Bell Richard B. , Weinberg Andrew D. 
Published: February 2019

Abstract
The immune system can recognize and destroy tumor cells through T-cell mediated mechanisms. Hence, identifying tumor antigen-specific T-cells from cancer patients and expanding them in large numbers in vitro has important implications for immunotherapy diagnostics and therapeutics. Here we show that tumor-reactive T-cells are enriched in a subset of tumor-infiltrating CD8 T-cells (CD8 TILs) identified by co-expression of CD103 and CD39 both in primary and metastatic tumors. The CD103+CD39+ CD8 TILs are present at high frequencies in melanoma and mismatch repair-deficient colon cancer but at low frequencies in microsatellite stable (MSS) colon cancer and colorectal liver metastasis. This cell population displays a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. Importantly, we show in a MSS colon cancer patient that a very low number of CD103+CD39+ CD8 TILs can be expanded in vitro and that those cells recognize tumor-specific neoantigens. Finally, patients with head and neck cancer whose CD8 TILs contained a higher frequency of CD103+CD39+ cells experienced a greater overall survival. Our work suggests that CD103+CD39+ CD8 TILs are key players in the patient’s antitumor response and describe an approach for detecting and expanding those cells, which will help improve adoptive TIL therapy for cancer patients.
Citation Format: Thomas Duhen, Rebekka Duhen, Ryan Montler, Tarsem Moudgil, Jitske van den Bulk, Bernard A. Fox, Shu-Ching Chang, Gary Grunkemeier, Els M.E. Verdegaal, Noel F. de Miranda, Rom Leidner, Richard B. Bell, Andrew D. Weinberg. A new strategy to identify and expand tumor-reactive CD8 TILs in human solid tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A186.
Abstract A196: Systematic identification of markers and drug targets on exhausted CD8+ T-cells
Authors: Hudson Will H. , Gensheimer Julia L. , Kissick Haydn T. , Ahmed Rafi 
Published: February 2019

Abstract
CD8+ T-cells are responsible for detection and killing of hosT-cells expressing non-self proteins. Upon antigen persistence, as in cancer or chronic viral infection, antigen-specific CD8+ T-cells lose their effector function, a phenomenon known as T-cell exhaustion. This process is concomitant with increased surface expression of negative regulatory proteins such as PD-1 and CTLA-4. Blockade of these molecules has become a widespread and successful clinical strategy for the treatment of malignancies. Unfortunately, not all tumor types are responsive to checkpoint molecule blockade, nor do all patients with susceptible tumor types exhibit clinical responses. These failures highlight the need for identification of additional negative regulators on exhausted, tumor-specific CD8+ T-cells. Here, we perform a systematic approach to identify surface proteins expressed on exhausted murine and human CD8+ T-cells. Using RNA-sequencing data from antigen-specific CD8+ T-cells from the mouse lymphocytic choriomeningitis virus (LCMV) infection model as well as data from human tumor-infiltrating CD8+ T-cells, we show high cross-species concordance of genes encoding membrane proteins in T-cell exhaustion. These expression profiles not only include many known checkpoint molecules such as PD-1, but also several proteins that negatively regulate T-cell receptor signaling but are largely unexplored in the process of CD8+ T-cell exhaustion. We validate these results performing by flow cytometry on both mouse and human CD8+ T-cells, including on T-cells obtained from resected human tumor tissue. To substantiate the importance of these markers, we further explore the function of one identified surface protein, CD101, in the murine LCMV infection model. We demonstrate that CD101 is induced on antigen-specific of CD8+ T-cells weeks after infection, in contrast with the early expression of canonical exhaustion markers such as PD-1. We show that antigen-specific CD101+ cells arise from CD101- precursors and that this differentiation process results in a loss of effector function, cytokine production, and proliferative capacity with simultaneous large transcriptomic changes. Together, these results demonstrate that exhaustion-associated surface protein expression patterns are largely conserved between humans and mice and provide a comprehensive catalog of phenotypic markers and potential drug targets for CD8+ T-cell-directed immunotherapy.
Citation Format: Will H. Hudson, Julia L. Gensheimer, Haydn T. Kissick, Rafi Ahmed. Systematic identification of markers and drug targets on exhausted CD8+ T-cells [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A196.
Abstract A211: Requirement of Treg-intrinsic CTLA4-PKCeta signaling pathway for suppressing tumor immunity
Authors: Pedros Christophe , Liu Hsin-Yu , Canonigo-Balancio Ann J. , Kong Kok-Fai , Altman Amnon 
Published: February 2019

Abstract
The ability of Tregs to control the development of immune responses is essential for maintaining immune system homeostasis. However, Tregs also inhibit the development of efficient antitumor immune responses. Here we explored the characteristics and mechanistic basis of the Treg-intrinsic CTLA4-PKCη signaling pathway that we recently found to be required for contact-dependent Treg-mediated suppression. We show that PKCη is required for the Treg-mediated suppression of tumor immunity in vivo. The presence of PKCη-deficient (Prkch-/-) Tregs in the tumor microenvironment was associated with a significantly increased expression of the costimulatory molecule CD86 on intratumoral CD103+ DCs, enhanced priming of antigen-specific CD8+ T-cells, and greater levels of effector cytokines produced by these cells. Tumor development was reduced similarly in Treg-specific (Prkch-flox x Foxp3-Cre) and globally deficient recipients (Prkch-/-) as compared to wt mice, indicating that PKCη expression by effector cells is dispensable for the development of efficient anti-tumor responses. Similar to mouse Tregs, the GIT-PAK-PIX complex also operated downstream of CTLA4 and PKCη in human Tregs, and GIT2 knockdown in Tregs promoted antitumor immunity. We are now exploring the therapeutic impact of PKCη deletion in tumor-bearing mice using tamoxifen treatment of Prkch-flox x Foxp3-ERT2Cre and Prkch-flox x UBC-ERT2Cre mice as a surrogate for treatment with a highly selective and efficient PKCη inhibitor. Collectively, our data suggest that targeting the CTLA4-PKCη-GIT-PAK-PIX signaling pathway in Tregs could represent a novel immunotherapeutic strategy to alleviate the negative impact of Tregs on antitumor immune responses.
Citation Format: Christophe Pedros, Hsin-Yu Liu, Ann J. Canonigo-Balancio, Kok-Fai Kong, Amnon Altman. Requirement of Treg-intrinsic CTLA4-PKCeta signaling pathway for suppressing tumor immunity [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A211.
Abstract A226: Cell-free membrane reconstitution system for cis and trans interaction of T-cell co-receptors and ligands
Authors: Zhao Yunlong , Hui Enfu 
Published: February 2019

Abstract
Immunotherapy, which harnesses the immune system to combat cancers, is a paradigm-shifting approach in oncology. One important branch of immunotherapy is to use drugs to perturb molecular interactions at the T-cell–antigen presenting cell (APC) interface. In particular, antibodies that block the T-cell coinhibitory receptor PD-1 or its ligand PD-L1 have produced unprecedented clinical activities against a subset of human cancers in a fraction of patients. Extending immunotherapy to a larger patient population requires a better understanding of the interaction network at the T-cell-APC interface. Typically, it is believed that ligands from APCs bind to receptors on T-cells (in trans) to trigger intracellular signaling. A largely overlooked fact is that many receptors often co-exist with ligands on T-cells and APCs, including PD-1/PD-L1 and CD28/B7.1. Using novel reconstitution approaches, we recently discovered that co-expressed PD- 1 and PD-L1 bind to each other in cis and this cis interaction competes with their trans interaction to inhibit PD-1 signaling. We hypothesize that cis interaction occurs with many other ligand-receptor pairs and may regulate other aspects of tumor immunity by perturbing their trans interactions. We are currently using our robust reconstitution systems to ask whether other immunoreceptors and ligands interact in cis and how the putative cis interaction affect their trans interactions. Specifically, to detect cis interaction, we co-attach the ligand and receptor to liposomes, and probe their cis interaction using a fluorescence resonance energy transfer (FRET) readout. To detect trans interaction, we have developed a liposome-lipid bilayer conjugation assay, in which binding between ligand- labeled liposomes and receptor-labeled supported lipid bilayer (SLB) is used as an index for trans interaction. To determine whether cis interaction inhibits trans interaction, we ask in the liposome-bilayer system if addition of receptor on liposomes decreases liposome-SLB conjugation. Our preliminary data revealed that CD28 only binds B7.1 in trans, but not in cis. In contrast, PD-1 binds with PD-L1 both in cis and trans, and the two modes of interaction compete with each other. Further experiments in cells confirmed our finding in vitro, demonstrating the utility of our cell-free reconstitution systems in detecting cis and trans interaction of T-cell co-receptors. Insights from this study will help us clarify the ligand-receptor interaction network at the immunological synapse.
Citation Format: Yunlong Zhao, Enfu Hui. Cell-free membrane reconstitution system for cis and trans interaction of T-cell co-receptors and ligands [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A226.
Abstract B012: Characterizing tumor-induced exhaustion in melanoma patients treated with neoadjuvant pembrolizumab
Authors: Giles Josephine R. , Huang Alexander C. , Manne Saskinath , Henao-Meji Jorge , Wherry E. John 
Published: February 2019

Abstract
Immune checkpoint blockade, including anti-PD-1 therapies, has had unprecedented success in treating various forms of cancer, including melanoma. Yet the majority of patients do not achieve durable clinical remission. The limited understanding of how these therapies work at the cellular and molecular level prevents the optimization required to improve patient outcomes. We performed RNA-seq and ATAC-seq on four sorted T-cell subpopulations (naïve CD8 T-cells, non-naïve CD8, non-naïve CD4 T-cells, T regulatory cells) from patients with metastatic melanoma before and after pembrolizumab treatment. While there were no significant changes before and after treatment in the sorted peripheral blood populations, we identified many alterations in the tumor compared to the blood following treatment. These differences may represent impediments to fully reinvigorating exhausted T-cells and be potential targets for achieving more durable clinical responses. We identified a zinc finger gene, ZC3H12C, as not only one of the most highly upregulated in non-naïve CD8 T-cells in the tumor, but it also had the highest number of associated altered open chromatin regions. This gene and its locus are also significantly different in exhausted T-cells compared to effector and memory cells in a mouse model of chronic viral infection using Lymphocytic choriomeningitis (LCMV). This conservation between species suggest an important role in T-cell exhaustion and provided an avenue to test its function in vivo, so we generated ZC3H12C knockout mice using CRISPR-Cas9. Following C13 (chronic) LCMV infection, virus-specific P14 CD8 T-cells lacking ZC3H12C are unable to persist compared to wild type P14 cells. These results suggest ZC3H12C may be critical to the survival of exhausted T-cells in the tumor and their ability to persist after anti-PD1 treatment. Here, we used transcriptomic and epigenetic analysis of a clinical human cancer data set to identify a novel target and used reverse translation in a mouse model to validate its importance in T-cell exhaustion. This gene and more broadly this strategy have the potential to provide immediately useful targets for improving immunotherapies.
Citation Format: Josephine R. Giles, Alexander C. Huang, Saskinath Manne, Jorge Henao-Meji, E. John Wherry. Characterizing tumor-induced exhaustion in melanoma patients treated with neoadjuvant pembrolizumab [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B012.