bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA04: Impact of tumor-resident DC on antitumor immunity
Authors: Spranger Stefani 
Published: March 2020

Abstract
Clearance of tumors relies heavily on the production and maintenance of poly-functional CD8+ T-cell responses. Studies of antiviral and antitumor responses highlight that loss of T-cell effector functions, a phenomenon termed T-cell dysfunction or exhaustion, is associated with tumor evasion and is characteristic of a failed immune response. While this correlation is widely appreciated and the T cell-intrinsic mechanisms are well understood, our current understanding of the T cell-extrinsic stimuli that determine T-cell dysfunction versus sustained effector function remains rudimentary. Studies highlight that T-cell dysfunction is induced in tissue microenvironments characterized by high antigen density such as the tumor or the tumor-draining lymph node. Recent studies using mouse models and patient samples suggest that tumor-resident dendritic cells (DC) can have extensive impact on effector T-cell recruitment and function. Based on these observations, it is conceivable that local, nonmigratory DC subsets can engage directly with antigen-specific T cells and impact their effector function by supplying stimulatory or inhibitory signals. We have established model systems of cancer recapitulating the optimal, immunotherapy-sensitive, and immunotherapy-resistant phenotypes. Our data suggest that optimal antitumor immune responses are associated with the presence of a novel subset of DC, which we termed interferon-stimulated gene (ISG)-DC. Our data highlight that ISG-DC are a distinct subset of DC, capable of activating CD8+ T cells and providing a distinct set of costimulatory molecules to re-engage T cells. Mechanistic studies highlight that ISG-DC use an unconventional way of antigen presentation and are sensitized by tumor-derived dsRNA. In sum, we have identified a novel DC subset, which should be further explored for therapeutic engagement.
Citation Format: Stefani Spranger. Impact of tumor-resident DC on antitumor immunity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA04.
Abstract IA06: Optimizing T-cell receptor gene therapy for cancer
Authors: Chapuis Aude G. 
Published: March 2020

Abstract
My lab is translating T-cell receptor (TCR)-engineered T-cell therapies for patients with solid and liquid tumors, working to understand relevant immune escape mechanisms and developing strategies to circumvent obstacles to clinical efficacy. To advance optimally safe and effective TCRs, we devised a system to identify the highest-affinity TCRs from the pooled peripheral repertoires of human leukocyte antigen (HLA)-matched donors, from which autoreactive clones had been removed by thymic selection. In the solid-tumor realm, we developed adoptive T-cell therapy for patients with Merkel cell carcinoma (MCC), a virus-driven cancer that is an ideal model to test TCR-based treatments targeting non-self epitopes. We treated patients using autologous Merkel cell polyomavirus (MCPy)-specific CD8+ T-cell lines and an immune checkpoint inhibitor. Dramatic tumor reductions were associated with dense infiltrates of activated T cells in two patients, but relapses occurred 22 and 18 months later. Single-cell RNA sequencing (scRNAseq) identified dynamic transcriptional suppression of the targeted HLAs, suggesting strong and specific immunologic pressure of therapeutic T cells. To address HLA downregulation as a tumor escape mechanism, we have initiated a trial utilizing a high-affinity HLA A*0201-restricted TCR to engineered autologous T cells, thus conferring a high-affinity TCR to all patients. As soon as safety is confirmed with this TCR alone, T cells carrying other MCPy-targeting TCR(s) with alternate HLA restrictions will be combined. Overall, revealing the in vivo escape mechanisms that undermine the efficacy of transgenic T-cell therapy in patients can inform significant improvements in the design of TCR-engineered immunotherapies.
Citation Format: Aude G. Chapuis. Optimizing T-cell receptor gene therapy for cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA06.
Abstract IA08: Understanding resistance to develop next-generation CART for lymphoid malignancies
Authors: Ruella Marco 
Published: March 2020

Abstract
Adoptive T-cell therapies, and in particular chimeric antigen receptor T cells (CART), are leading to significant responses in cancer patients, particularly in B-cell leukemias and lymphomas. However, a significant subset of patients still do not respond or eventually relapse after anti-CD19 CART therapy. In his talk, Dr. Ruella will highlight recent finding in the pathogenesis of relapse after CART19 and discuss novel therapeutic approaches aimed at increasing CART feasibility and efficacy.
Citation Format: Marco Ruella. Understanding resistance to develop next-generation CART for lymphoid malignancies [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA08.
Abstract IA12: Epigenetic therapy—potential efficacy for enhancing immune checkpoint therapy
Authors: Baylin Stephen B. 
Published: March 2020

Abstract
Despite the tremendous contribution made to date by immune checkpoint therapy to cancer management, most patients with the most common and deadliest forms of advanced cancer still do not receive durable benefit. Achieving manifest responses initially, understanding what predicts and contributes to long-term overall survival, and how to reverse initial or evolved resistance are all still major challenges to be addressed. Developing combinatorial approaches that may contribute to all of the above issues is a major goal, and epigenetic therapy is in play as one strategy for this purpose. Key specific points of the overall potential for the merits of combining this latter approach with immune checkpoint and other immunotherapies will be discussed in this presentation and include: 1) Critical steps in tumor immune evasion are under epigenetic control and can be reversed experimentally. There is evidence emerging that this also may be accomplished in patients and with epigenetic therapy drugs clinically available and in clinical trials such as DNA methyltransferase (DNMTis) and histone deactylase inhibitors (HDACis). The above steps for these drugs include restoration of tumor antigen presentation processes, restoration of tumor cell signaling for attraction of key antitumor subsets of immune cells, repulsion from tumors of key cells that promote immune tolerance, and repression of key oncogenic signaling pathways that otherwise suppress these above tumor immune attraction signals. 2) Key facets of immune tolerance inherent to signaling in immune cell subsets are under the control of epigenetic processes, and these too can be reversed by the types of drugs listed above, including T-cell and other immune cell exhaustion signaling, behavior of key ligands and receptors on immune cells critical for their migration to tumor cell sites and attack of cancer cells. Key experimental data for the above processes, coming from our own lab group and many collaborations within our participation in the Van Andel Institute – Stand Up To Cancer (VAI-SU2C) epigenetic therapy dream team, will be presented to support the hypotheses articulated above. Barriers to achieving efficacy of the approach, including which drugs will ultimately prevail, how to best sequence administration of the drugs, what cancer stages are most optimal for therapy institution, and what molecular parameters are promising for predicting efficacy, will also be discussed.
Citation Format: Stephen B. Baylin. Epigenetic therapy—potential efficacy for enhancing immune checkpoint therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA12.
Abstract IA13: Reprogramming the epigenome for enhancing CAR T-cell antitumor efficacy
Authors: Fraietta Joseph A. 
Published: March 2020

Abstract
Many studies indicate that adoptive cell transfer therapy with autologous chimeric antigen receptor (CAR) T cells is a powerful approach for the treatment of cancer. CAR-modified T cells have shown activity in several clinical trials including our own at the University of Pennsylvania, with complete response rates as high as 80-90% in certain malignancies. However, the effectiveness of this approach for cancers involving T-cell defects, such as multiple myeloma, pancreatic cancer, and chronic lymphocytic leukemia (CLL), is much lower. The key questions currently facing the field are how to: i) enhance the potency and sustain the in vivo function of CAR T cells for such indications and ii) develop strategies to increase the resistance of CAR T cells to intrinsic and extrinsic dysfunction (e.g., immunosenescence, exhaustion, or other disease-specific defects). Because cell fate determination programs encoded in DNA are interpreted, modified, transmitted, and expanded as chromatin, we hypothesize that immunotherapy and reversal of T-cell dysfunction in cancer can be improved by broadly or specifically targeting appropriate epigenetic pathways. In this vein, we explore manipulation of the “writers” and “readers” of the histone code using genetic editing tools (e.g., CRISPR/Cas9) and chemical modifiers to convert poorly functional T cells to a state that renders these lymphocytes effective at tumor elimination. The basic understanding of T-cell biology in the context of epigenetic regulation may result in enhancement of cellular immunotherapy strategies, including the discovery of several actionable improvements to CAR T-cell therapy.
Citation Format: Joseph A. Fraietta. Reprogramming the epigenome for enhancing CAR T-cell antitumor efficacy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA13.
Abstract IA16: Whole-body PD-L1 and PD-1 PET: First-in-human experience
Authors: Leung David 
Published: March 2020

Abstract
Interaction between PD-L1 and PD-1 is central to the mechanism of action of, as well as prognostic and predictive to, PD-(L)1 immune checkpoint inhibition (ICI) therapy in non-small cell lung cancer (NSCLC). PD-L1 expression determined by immunohistochemistry (IHC), however, correlates moderately with patient survival and response to anti PD-(L)1 ICI. This discrepancy may be because of sampling errors from the spatial heterogeneity of tumor PD-L1 expression. Here we show that PD-L1 and PD-1 PET imaging can (1) visualize whole-body PD-(L)1 expression in patients with NSCLC, (2) specifically, revealing expression heterogeneity within tumors as well as among tumors within the same patient, and (3) demonstrate in vivo interactions between PD-L1 expression and anti PD-1 ICI, thus enhancing our understanding of tumor biology toward ICI.
Citation Format: David Leung. Whole-body PD-L1 and PD-1 PET: First-in-human experience [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA16.
Abstract IA17: AI-powered pathology for precision medicine
Authors: Beck Andrew H. 
Published: March 2020

Abstract
Pathologic analysis of patient tissue specimens plays a central role in the field of oncology. Recent advances in artificial intelligence and computer vision offer tremendous potential for discovering new pathologic mechanisms of cancer treatment response and identifying new diagnostics for matching patients and therapies. We will discuss these new advances and their potential for accelerating progress in the diagnosis and treatment of cancer, with a focus on immuno-oncology and therapies targeting the PD-1/PD-L1 pathway.
Citation Format: Andrew H. Beck. AI-powered pathology for precision medicine [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA17.
Abstract IA20: Chromatin state and scRNA-seq analysis defines a common differentiation trajectory towards T-cell exhaustion
Authors: Leslie Christina 
Published: March 2020

Abstract
We will describe a unified chromatin state and single cell expression analysis underlying T-cell differentiation to “exhaustion.” Numerous studies in chronic viral infection and tumor models have shown that most T cells progress to a terminally dysfunctional (“exhausted”) state from which they cannot be rescued by current immunotherapies. We performed a systematic analysis of over 280 ATAC-seq and RNA-seq experiments from eight published studies of CD8 T cell dysfunction, using a statistical batch correction to define a common differentiation trajectory to terminal exhaustion in all settings of chronic antigen exposure and to identify transcription factors involved in this progression. We further performed scRNA-seq analysis of CD8 T cells at multiple time points during acute and chronic viral infection and in adoptive cell transfer studies to elucidate this trajectory at single-cell resolution.
Citation Format: Christina Leslie. Chromatin state and scRNA-seq analysis defines a common differentiation trajectory towards T-cell exhaustion [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA20.
Abstract IA23: The role of the microbiome in response and toxicity to cancer therapy
Authors: Wargo Jennifer A. 
Published: March 2020

Abstract
We have made tremendous progress in cancer care via the use of immunotherapy; however, not all patients respond and toxicity to therapy may be limiting. It is becoming increasingly clear that responses to therapy are dependent on a number of factors that influence tumor growth and immunity—and that these all are inter-related. There is a growing appreciation of the role of environmental factors, such as the microbiome, on responses to therapy. The microbiome refers to microbes and their genomes within a given host, and there is a significant contribution of microbes to our overall cellular content and to our genomic content. There is now evidence that the gut microbiome may shape immunity and responses to immunotherapy, and efforts are ongoing to modulate the microbiome to enhance therapeutic responses. Additionally, there is evidence that microbes within tumors of patients with cancer may shape responses to therapy. Furthermore, microbes may also influence toxicity to cancer therapy. The use of the microbiome as a biomarker and a therapeutic target will be discussed, as will complexities and recommendations for a path forward to implement microbiome analyses and targeting in precision cancer care and overall precision health.
Citation Format: Jennifer A. Wargo. The role of the microbiome in response and toxicity to cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA23.
Abstract PR11: Antigen dominance hierarchies shape tumor T-cell phenotypes and immunotherapy responses
Authors: Burger Megan L. , Crossland Grace E. , Schenkel Jason M. , Canner David A. , Jacks Tyler 
Published: March 2020

Abstract
In order to drive a productive T-cell response to checkpoint immunotherapy, tumors must be sufficiently antigenic. However, antigens vary in their degree of immunogenicity and consequently drive T-cell responses of different magnitudes and quality. In a genetically engineered mouse model of lung adenocarcinoma expressing model T-cell antigens, we find that antigen dominance hierarchies are established in tumors, where the T-cell response is largely focused on a dominant epitope as observed in viral infections. Interestingly, while T cells responding to a subdominant antigen are fewer in number, we find that they are less exhausted and express more markers of memory cells. T cells responding to the dominant antigen rapidly contract, while those responding to the subdominant antigen persist better over time. Despite their seemingly greater functional potential, T cells responding to the subdominant antigen fail to respond significantly to checkpoint immunotherapy in the context of this dominance hierarchy. Remarkably, removal of the dominant antigen unleashes the subdominant response and these cells expand to fill the effector niche previously occupied by the dominant response. Current experiments are testing the ability of vaccination to “break dominance” and improve the contribution of the subdominant response to tumor control. These findings could have great relevance to the design of personalized cancer vaccines, where targeting subdominant antigens over dominant antigens may lead to surprising therapeutic benefit.
This abstract is also being presented as Poster B36.
Citation Format: Megan L. Burger, Grace E. Crossland, Jason M. Schenkel, David A. Canner, Tyler Jacks. Antigen dominance hierarchies shape tumor T-cell phenotypes and immunotherapy responses [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR11.
Abstract PR12: Genomic landscape of immunotherapy resistance in lung cancer
Authors: Lau Denise , Stein Michelle , Perera Jason , Kannan Madhavi , Khan Aly 
Published: March 2020

Abstract
Immune checkpoint inhibitors (ICI) have emerged as an important modality in lung cancer treatment. However, studies have shown that only a fraction of patients will experience any clinical benefit when treated with ICI, and a better understanding of the mechanisms of resistance is still needed. In this study, we sought to characterize the prevalence of known mechanisms of primary and adaptive resistance in the context of the greater immunogenomic landscape in a real-world cohort of 100 non-small cell lung cancer patients treated with ICI. Targeted panel DNA sequencing and whole-transcriptome RNA sequencing were performed on a primary tumor biopsy for each patient, the clinical notes were abstracted and structured, and the digital image of the H&E was processed through a tumor-infiltrating lymphocyte (TIL) analysis pipeline. We evaluated each tumor for evidence of HLA loss of heterozygosity (LOH), mutations in the antigen presentation or interferon gamma signaling pathways, expression of alternative checkpoint molecules, and immune infiltrate exclusion. We found that over 25% of patients in the cohort showed signs of at least one of these mechanisms of ICI resistance. We evaluated the real-world progression-free survival (rwPFS) for these patients and found that the majority experienced a progression event within 6 months of treatment start. This study suggests that primary resistance to ICI affects a significant population of lung cancer patients.
This abstract is also being presented as Poster B22.
Citation Format: Denise Lau, Michelle Stein, Jason Perera, Madhavi Kannan, Aly Khan. Genomic landscape of immunotherapy resistance in lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR12.
Abstract PR9: Loss of PD-1 promotes antitumor immunity by improving functions of both PD-1+ and PD-1- CD8+ T cells in the tumor microenvironment
Authors: Pauken Kristen E. , Juneja Vikram R. , Ringel Alison , Rowe Jared H. , Burke Kelly P. , Sage Peter T. , LaFleur Martin W. , Kuchroo Juhi R. , Ron-Harel Noga , Maleri Seth , Long Jaclyn M. , Freeman Gordon J. , Chevrier Nicolas , Haigis Marcia C. , Sharpe Arlene H. 
Published: March 2020

Abstract
Although PD-1 pathway inhibitors are revolutionizing cancer treatment, the mechanisms by which PD-1 regulates antitumor immunity are not fully understood. To determine PD-1 functions on different cell types, we used PD-1 conditional knockout mice. Subcutaneous transplantation of MC38 adenocarcinoma tumor cells in mice with complete deletion of PD-1 selectively on CD8+ T cells improved CD8+ T functions in the tumor microenvironment (TME). CD8+ T cells were required for the protective effects of PD-1 deletion in this model. To assess whether loss of PD-1 on all cells was necessary for improved antitumor immunity, we restricted PD-1 deletion to only half of the T-cell population. We hypothesized that a cell-intrinsic loss of PD-1 was necessary for improved T-cell fitness and effector functions. Here, deletion of PD-1 indeed led to T cell-intrinsic boosts in function. Unexpectedly, however, there was also a bystander effect that improved functions of PD-1-expressing CD8+ T cells in the TME. These data suggest that complete loss of PD-1 is not necessary for optimal tumor immunity, a finding that has important implications for applying PD-1-based immunotherapies to cancer patients.
This abstract is also being presented as Poster B82.
Citation Format: Kristen E. Pauken, Vikram R. Juneja, Alison Ringel, Jared H. Rowe, Kelly P. Burke, Peter T. Sage, Martin W. LaFleur, Juhi R. Kuchroo, Noga Ron-Harel, Seth Maleri, Jaclyn M. Long, Gordon J. Freeman, Nicolas Chevrier, Marcia C. Haigis, Arlene H. Sharpe. Loss of PD-1 promotes antitumor immunity by improving functions of both PD-1+ and PD-1- CD8+ T cells in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR9.
Rediscovery of Epilobium trichophyllum Hausskn.: a rare and endemic plant from Sikkim Himalaya, India
Authors: Biate David L. , Agrawala Dinesh K. 
Published: March 2020

Epilobium trichophyllum Hausskn., is a rare and endemic plant known only from its type collection [Sikkim (10-12000 ft.), Latung (Lachung), 13.vii.1849, J.D. Hooker & Thomson 7 (K- Royal Botanic Garden, Kew; W - Naturhistorisches Museum Wien, Vienna)]. An unidentified specimen at BSHC [Pradhan & Giri 29191A (BSHC!)] with characteristic villous hairs throughout the plant could be determined as Epilobium trichophyllum Hausskn. This specimen was collected in 2006 (after a gap of 157 years) from Zema-1 on the way from Lachen to Thangu with similar phyto-climatic condition as that of the type locality. A brief description, taxonomic history and photograph of the specimens have been provided to confirm its identity. Its threat status has been assessed as ‘Critically Endangered’ as per IUCN Red List criteria.
New records of Heloderma alvarezi (Wiegmann, 1829) (Sauria: Helodermatidae) on the coast of Oaxaca and increases to its distribution in Mexico
Authors: Garcia-Grajales Jesús , Arrazola Bohórquez Rodrigo , Penguilly Macías María Arely , Buenrostro Silva Alejandra 
Published: March 2020

This work provides three new photographic records and evidence of increase in distribution of Heloderma alvarezi based on different encounters between human activities and the displacement of this species along the central coast of Oaxaca, Mexico. Until now, this species occurred only in Chiapas State, however, the new records provide information about the increase in species distribution on the coast of Oaxaca, so this has increased the number of reptiles in Oaxaca to 448 species.