bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A110: Efficacy of anti-PD1 immune checkpoint blockade involves the cooperative interaction of myeloid and lymphoid subpopulations in the tumor microenvironment
Authors: Schetters Sjoerd , Kooyk Yvette Van 
Published: February 2019

Abstract
Suppression of the immune system by solid malignancies has proven to be a driving force of tumor development and an effective target for therapeutic intervention. The suppression of cytolytic T-cells by inhibitory receptors like PD1 can be blocked by antagonistic antibodies, reinvigorating suppressed antitumor responses. Nonetheless, only a minority of patients show clinical benefit. It is becoming clear the efficacy of checkpoint blockade relies on many factors, including pretreatment conditions, collaboration between innate and adaptive immune cells and immune-architecture of the tumor microenvironment (TME). To investigate this, we studied the immune profiles of the PD1-unresponsive murine B16 melanoma and PD1-responsive MC38 colorectal carcinoma models, systemically and in the TME before and during treatment. By using high-dimensional flow cytometry and unsupervised clustering analyses based on immune checkpoints, we show comparable early establishment of heterogeneity of tumor-infiltrating CD8+ and CD4+ T-cells. However, PD1-responsive MC38 tumor shows correlations in abundance between specific CD8+ T-cell, NK cells and myeloid subsets before checkpoint blockade treatment, while the PD1-unresponsive B16 tumors do not show lymphoid-myeloid codependences. Interestingly, the abundance of monocyte-derived dendritic cells did not increase upon anti-PD1 treatment but instead showed abundance correlation with PD1 CD4+ and CD8+ T-cells, suggesting a putative interaction. The unresponsive B16 tumors showed increased correlation of cDC1 and cDC2 with Foxp3+ regulatory T-cells. We have visualized these putative interactions within the myeloid and lymphoid population in the changing immune-architecture of the TME, using multiplex fluorescence and confocal microscopy. We show heterogeneity and interactive hotspots during immune checkpoint blockade and postulate that successful anti-PD1 treatment requires the location-dependent cooperation of specific myeloid and lymphoid subsets in the TME.
Citation Format: Sjoerd Schetters, Yvette Van Kooyk. Efficacy of anti-PD1 immune checkpoint blockade involves the cooperative interaction of myeloid and lymphoid subpopulations in the tumor microenvironment [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 A110.
Abstract A122: Self-recognition of Alu duplex RNAs is the basis for MDA5-mediated interferonopathies
Authors: Ahmad Sadeem , Mu Xin , Hur Sun 
Published: February 2019

Abstract
Melanoma Differentiation Associated Gene-5 (MDA5) is an innate immune receptor that binds to viral double-stranded RNAs (dsRNAs) and initiates type I and III interferon signaling cascade thereby playing a key role in antiviral immune response. Recently, a number of mutations that lead to aberrant activation of MDA5 have been implicated in various autoinflammatory disorders including Aicardi-Goutières syndrome. The mechanistic basis of this constitutive MDA5 activation, however, has remained elusive. An understanding of the subtle balance of self vs. non-self discrimination by MDA5 is important, especially in the context of recent reports demonstrating the targeted activation of MDA5 as a potential therapeutic strategy against diverse carcinoma. Our work revealed a hitherto unknown role played by the RNA-rich cellular environment in preventing aberrant MDA5 activation by imposing cooperative filament assembly on dsRNAs as a functional requirement for signal activation. We further employed a novel RNase protection-RNAseq approach to show that the disease-causing gain-of-function (GOF) mutants of MDA5 can form signaling-competent filaments on endogenous RNA populations comprising mainly Alu RNA duplexes. Strikingly, under physiologic conditions, the wild type MDA5 is not activated by Alu RNAs because of its sensitivity to structural irregularities such as bulges and mismatches commonly occurring in Alu:Alu hybrids. The GOF mutants, on the other hand, show reduced sensitivity to disruptions in duplex RNA structures as revealed by our in-depth biochemical probing. Overall, the work reveals the underlying mechanism behind MDA5-mediated inflammatory disorders. Moreover, it highlights the unique role played by Alu RNAs as an evolutionary tether on MDA5, keeping its affinity towards “self” ligands under check during the course of evolution.
Citation Format: Sadeem Ahmad, Xin Mu, Sun Hur. Self-recognition of Alu duplex RNAs is the basis for MDA5-mediated interferonopathies [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 A122.
Abstract A123: Skewed CD4 and CD8 T-cell differentiation in pancreatic cancer patients
Authors: Alanio Cecile , Bengsch Bertram , Gies Josephine R. , Henrickson Sarah , Weng Nan Ping , Ritz-Romeo Janáe A , O'Hara Mark , Melenhorst Joseph J , Lacey Simon , Young Regina M , June Carl H , Wherry E. John 
Published: February 2019

Abstract
To understand potential immune system alterations in newly diagnosed, untreated, pancreatic cancer patients and provide a foundation for immunotherapy, we profiled PBMC from pancreatic ductal adenocarcinoma (PDA) patients and age-matched healthy controls using high-dimensional CyTOF analysis. We developed two immune profiling panels: a broad profiling panel that includes 45 phenotypic markers that together permit the identification and enumeration of the main innate and adaptive immune cell subsets in humans, and a deep profiling panel that includes 45 features focusing on T-cell phenotype and biology. We report a 2-fold increase in monocytes, more regulatory T-cells, and more plasmocytes in circulation in pancreatic cancer patients as compared to age-matched controls, as well as a bias towards cytokine-producing NK cells. Using high-dimensional approaches, we observed skewed T-cell differentiation in pancreatic cancer patients, with peripheral blood CD8 T-cells being biased towards more CD45RA-positive CD27-positive CCR7-positive CD95-positive CD49d-positive stem cell memory cells (P=7x10-5), more CD45RA-negative CD27-positive CCR7-negative effector memory cells (P=0.002) and less CD45RA-positive CD27-negative CCR7-negative late effector memory cells (P=0.003) as compared to age-matched controls. Strikingly, when examinating T-cell differentiation in human spleens, we found increased proportions of late effector memory T-cells in the splenic CD8 T-cell compartment of pancreatic cancer patients as compared to age-matched controls. These results suggest an impaired T-cell trafficking in pancreatic cancer patients, with late memory T-cells being retained in the spleen. We are now investigating the mechanisms underlying these observations, as well as their impact on T-cell immunity of the cancer patients. Our goal is to understand the nature of the skewing and how any changes in baseline immune health of the T-cell compartment relate to disease progression and/or response to therapy. These studies should provide a foundation for improving therapy in pancreatic cancer patients.
Citation Format: Cecile Alanio, Bertram Bengsch, Josephine R. Gies, Sarah Henrickson, Nan Ping Weng, Janáe A Ritz-Romeo, Mark O'Hara, Joseph J Melenhorst, Simon Lacey, Regina M Young, Carl H June, E. John Wherry. Skewed CD4 and CD8 T-cell differentiation in pancreatic 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 A123.
Abstract A128: Tumor endothelial cells say IDO to CD40-stimulating immunotherapy
Authors: Dimberg Anna , Karampatzakis Alexandros , Tuit Sander , Ramachandran Mohanraj , Fotaki Grammatiki , Hooren Luuk van , Huang Hua , Lugano Roberta , Aura Kaunisto , Ellmark Peter , Mangsbo Sara M , Schultze Joachim L. , Essand Magnus , Georganaki Maria 
Published: February 2019

Abstract
CD40, a tumor necrosis factor receptor superfamily member, is a promising immune-boosting target in cancer immunotherapy due to its role in promoting antitumor responses of immune cells. CD40 is also expressed on endothelial cells but the response of the tumor-associated vasculature to CD40-stimulating immunotherapy has not been studied. Herein, we have performed RNA-sequencing analysis of murine tumor endothelial cells (TECs) isolated from B16.F10 melanoma and MB49 bladder cancer treated with agonistic CD40 monoclonal antibody (mAb) or isotype control. Gene set and gene ontology enrichment analyses of the differentially expressed genes revealed that CD40 mAb treatment induces interferon-γ (IFNγ) signaling in the tumor microenvironment associated with up-regulation of immunosuppressive genes in TECs, including the enzyme indoleamine 2, 3-dioxygenase 1 (IDO1). Importantly, IDO1 was preferentially expressed in endothelial cells in the tumor and was positively correlated to infiltration of T-cells in the tumor microenvironment. In vitro, endothelial cells up-regulated IDO1 in response to T-cell-derived IFNγ, but not in response to CD40-stimulation. Collectively, our data suggest that IDO1 up-regulation in TECs occurs as a response to T-cell activation. Combining CD40 mAb therapy with the IDO1 inhibitor epacadostat delayed tumor growth and increased survival of B16.F10 tumor-bearing mice, which was associated with increased activation of cytotoxic T-cells. Hereby, we have uncovered a novel immunosuppressive feedback mechanism, in which the tumor vasculature limits the response to cancer immunotherapy by up-regulating IDO1.
Citation Format: Anna Dimberg, Alexandros Karampatzakis, Sander Tuit, Mohanraj Ramachandran, Grammatiki Fotaki, Luuk van Hooren, Hua Huang, Roberta Lugano, Kaunisto Aura, Peter Ellmark, Sara M Mangsbo, Joachim L. Schultze, Magnus Essand, Maria Georganaki. Tumor endothelial cells say IDO to CD40-stimulating immunotherapy [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 A128.
Abstract A148: A hydrogel platform for the delivery of specialized pro-resolving mediators to treat chronic inflammatory disease
Authors: Pillai Padmini Sushila , Webster Jamie , Langer Robert 
Published: February 2019

Abstract
The resolution of acute inflammation is an active process orchestrated by mediators that prevent further recruitment of inflammatory cells and promote clearance of microbes and dying cells. Chronic inflammation can arise when resolution is diminished due to a scarcity of these pro-resolving mediators. Current immunosuppressive drugs for the treatment of chronic inflammatory diseases such as IBD, arthritis, or psoriasis temporarily block inflammation without initiating resolution or tissue repair, leading to the recurrence of chronic inflammation. Additionally, systemic administration of these drugs leaves patients susceptible to tuberculosis, lymphoma, and opportunistic infections. Resolvins are a class of evolutionarily conserved lipid mediators that return tissue to homeostasis without immunosuppression by promoting phagocytosis of debris and microbes, and preventing proinflammatory cytokine production and cellular infiltration. To enhance dose sparing and stability, we have developed a tunable hydrogel platform to deliver resolvins to various sites of chronic inflammation. For oral delivery, this hydrogel is further encapsulated into a pH-sensitive microparticle formulated using anionic polymers, to target the large intestine. Using a mouse model of colitis, we demonstrate the ability of the hydrogel to resolve intestinal inflammation, initiate repair of the intestinal barrier, and regulate the gut microbiota. Our tunable hydrogel platform could have profound effects on the prevention of gastrointestinal cancers and chronic inflammatory disease.
Citation Format: Padmini Sushila Pillai, Jamie Webster, Robert Langer. A hydrogel platform for the delivery of specialized pro-resolving mediators to treat chronic inflammatory disease [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 A148.
Abstract A152: Investigating metabolic basis of neurotoxicity during CAR-T therapies
Authors: Salloum Darin , Santomasso Bianca , Brentjens Renier J. , Wendel Hans-Guido 
Published: February 2019

Abstract
Chimeric antigen receptor T (CAR-T) cell therapies are rapidly becoming first in line therapies for treatment of hematologic malignancies. This is due to the efficacy of the treatment and long-lasting tumor responses. However, CAR-T therapies are associated with unique set of acute toxicities— cytokine release syndrome (CRS) and neurologic toxicities—the cause of which is not clear. As other immune therapies are becoming more widely used, these toxicities are observed in patients undergoing bispecific T-cell engaging antibodies (BiTEs) and checkpoint blockade therapies. Here, we sought to define metabolic changes in patients undergoing chimeric antigen receptor (CAR) T-cell therapy for B-acute lymphoblastic leukemia. We performed metabolic analysis of amino acids in serum samples, and identified significant up-regulation of tryptophan-kynurenine metabolism in patients with high-grade neurotoxicity. In-depth look at tryptophan-kynurenine pathway in cerebrospinal fluid patient samples determined quinolinic acid up-regulation to correlate with low- and high-grade neurotoxicity, indicating local production of this metabolite. We show that quinolinic acid is produced by activated monocytes and microglia in response to Il1beta and TNF. Importantly, tryptophan metabolite—kynurenine— stimulates Il1beta production and further activation of monocytes, possibly exacerbating CSR and neurotoxicity. This study suggests that inhibition of tryptophan-kynurenine pathway may offer some benefit to manage neurotoxicity and CRS associated with CAR-T-cell therapy treatment.
Citation Format: Darin Salloum, Bianca Santomasso, Renier J. Brentjens, Hans-Guido Wendel. Investigating metabolic basis of neurotoxicity during CAR-T therapies [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 A152.
Abstract A169: Macrophage targeted zoledronic acid conjugated biomineral nanoparticles for γδT-cell-based cancer immunotherapy
Authors: Ashokan Anusha , Anoop Minu , Surendran Siju , Balakrishnan Aparna , Anna Ida M. , Ramkumar Anjana , Madathil Girish Chundayil , Harish Vijay , Koyakutty Manzoor 
Published: February 2019

Abstract
Nanoparticle platforms can be engineered to deliver immune-stimulatory molecules to specific immune cell populations, thereby evoke desired response. Here, we present a novel biomineral nanoparticle system for macrophage specific delivery of bisphosphonate molecules to evoke activation of γδ T-cells for cancer immunotherapy. Generally, γδ T-cells therapy is implemented either by ex vivo expansion followed by adoptive transfer or by in vivo activation using intravenous injection of bisphosphonates. One of the major limitations of intravenously injection of bisphosphonates such as zoledronic acid is its unfavorable biodistribution in the skeletal system due to covalent binding with calcium in the bone. In the present work, we have pre-conjugated zoledronic acid in a calcium-containing biomineral nanoparticle (Zol-BM) that has spontaneous specificity towards macrophages in the liver, spleen and lymph nodes. This enabled targeted expression of γδT-cell stimulating ligand, isopentyl pyrophosphate, in macrophages, leading to enhanced activation of γδT-cells. Optimized Zol-BM showed a drug conjugation efficiency of ~95% with particle size ~ 100 nm and zeta potential, -15mV. The compatibility of Zol-BM was tested in primary human peripheral blood mononuclear cells and macrophages cell lines. The biodistribution analysis of Zol-BM in healthy rat models showed accumulation in liver, spleen and lymph nodes which was confirmed by MRI and Prussian-blue analysis. Flow cytometry based γδT-cell proliferation analysis gave ~18% enhancement in γδ T-cell subset compared to untreated control. Thus, we show that by rational design of engineered nanoparticles, specific immuno-stimulatory molecules like zolendronate can be delivered to desired immune cells of interest (macrophages) for activating another sub-population of immune cells such as γδ T-cells, for cancer-immunotherapy applications.
Citation Format: Anusha Ashokan, Minu Anoop, Siju Surendran, Aparna Balakrishnan, Ida M. Anna, Anjana Ramkumar, Girish Chundayil Madathil, Vijay Harish, Manzoor Koyakutty. Macrophage targeted zoledronic acid conjugated biomineral nanoparticles for γδT-cell-based cancer immunotherapy [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 A169.
Abstract A172: Cxcr6-deficiency impairs cancer vaccine efficacy and resident memory CD8+ T-cells recruitment in tumor
Authors: Karaki Soumaya , Blanc Charlotte , Tran Thi , Galy-Fauroux Isabelle , Anson Marie , Golub Rachel , Tartour Eric 
Published: February 2019

Abstract
Immunization route is directly correlated with cancer vaccine efficacy. Our team previously showed that mucosal (intranasal, i.n.) and systemic (intramuscular) vaccinations are both able to induce systemic specific CD8+ T-cells but only i.n. immunization allows an efficient control of mucosal tumor growth. Indeed, the i.n. vaccination favors the tumor infiltration of specific CD8+ T-cells and especially tissue-resident memory T-cells (Trm), which are crucial for a potent antitumor activity. Based on a transcriptomic analysis, we have identified a chemokine receptor, CXCR6, highly expressed by these specific Trm CD8+ T-cells, induced by the i.n. vaccination. To understand the role of CXCR6 in vaccination efficacy, we have set up a body of experiments using heterozygous Cxcr6gfp/+ mice, where GFP reflects CXCR6 expression and homozygous Cxcr6-deficient mice Cxcr6gfp/gfp.We have then confirmed CXCR6 expression on specific Trm CD8+ T-cells induced by i.n. vaccination in lung mucosa. Using an orthotopic head and neck tumor model, CXCR6 expression on tumor-infiltrating Trm induced by i.n. immunization has also been reported. In addition, we showed that Cxcr6-deficiency impairs mice survival in a prophylactic and therapeutic i.n. vaccination settings in various mucosal tumor models. In this Cxcr6-deficient mouse model, the loss of vaccine-induced protection against tumor graft correlates with a clear reduction of Trm infiltration in tumor. Finally, in a cohort of human lung cancer, we have observed endogenous CXCR6+ Trm infiltrating these tumors in situ. To conclude, we have identified CXCR6 as a required parameter to recruit the crucial anti-tumor Trm in mucosal tumor. Our results finally indicate that CXCR6 might be a new surrogate biomarker to evaluate antitumor vaccine efficacy.
Citation Format: Soumaya Karaki, Charlotte Blanc, Thi Tran, Isabelle Galy-Fauroux, Marie Anson, Rachel Golub, Eric Tartour. Cxcr6-deficiency impairs cancer vaccine efficacy and resident memory CD8+ T-cells recruitment in tumor [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 A172.
Abstract A180: HHLA2 is a novel tumor-expressed member of the B7 immune checkpoint family
Authors: Chinai Jordan Manek , Wang Hao , Tang Xudong , Janakiram Murali , Cheng Haiying , Zang Xingxing 
Published: February 2019

Abstract
The purpose of this study was to assess the function and expression-regulation of the new B7 family member, HHLA2, in the tumor microenvironment. HHLA2 is a newly identified B7 family member that has been reported to both inhibit and stimulate T-cell function in vitro. Expression of HHLA2 has been noted on a wide variety of cancers and relatively few normal tissues. The function of HHLA2 in the tumor microenvironment remains elusive and the mechanisms regulating its expression are currently unknown. Challenges to addressing these questions include the lack of a functional HHLA2 gene in mice and, consequently, the lack of in vivo tumor models in which HHLA2 can be studied. Here we assess factors that drive expression of HHLA2 in vivo and present the first humanized mouse model to study the function of HHLA2 expression in the tumor microenvironment. Human cancer cell lines derived from lung, prostate, pancreas, kidney, and colon malignancies were identified with varying levels of HHLA2 expression. HHLA2 surface expression was monitored as these cell lines were grown in vivo as tumors in NSG mice and in vitro under conditions including cytokine stimulation, 3D culture, and hypoxia. Expression was assessed by both flow cytometry and qPCR. HHLA2-knockout cancer cell lines and controls were generated using CRISPR and grown as tumors in NSG mice with human immune cells. These tumors were dissociated and the immune infiltrates were phenotyped by flow cytometry. HHLA2 was upregulated in numerous human cancer cell lines in vivo and expression was reduced or lost in vitro under standard cell culture conditions. Conditions mimicking the tumor microenvironment including 3D culture, hypoxia, and cytokine stimulation all contributed to HHLA2 upregulation. We successfully generated HHLA2-knockout human cancer cell lines and developed a humanized tumor immunotherapy model. HHLA2-expressing tumors contained significantly less infiltrating CD8 and CD4 T-cells than the HHLA2-knockout tumors. The T-cells were also phenotypically less active in the HHLA2-expressing tumors. Expression of HHLA2 in human cancers is driven by environmental conditions that are specific to the tumor microenvironment and this expression appears to have a suppressive effect on infiltrating T-cells. HHLA2 is the newest B7 family member and a promising candidate for targeted immunotherapy against a wide range of cancers.
Citation Format: Jordan Manek Chinai, Hao Wang, Xudong Tang, Murali Janakiram, Haiying Cheng, Xingxing Zang. HHLA2 is a novel tumor-expressed member of the B7 immune checkpoint family [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 A180.