bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A33: High-throughput prediction of MHC Class I and Class II neoantigens with MHCnuggets
Authors: Shao Xiaoshan M. , Bhattacharya Rohit , Huang Justin , Sivakumar Ashok , Tokheim Collin , Zheng Lily , Hirsch Dylan , Kaminow Ben , Omdahl Ashton , Bonsack Maria , Riemer Angelika B. , Velculescu Victor E. , Anagnostou Valsamo , Pagel Kymberleigh , Karchin Rachel 
Published: March 2020

Abstract
Computational prediction of binding between neoantigen peptides and major histocompatibility complex (MHC) proteins is an emerging biomarker for predicting patient response to cancer immunotherapy. Current neoantigen predictors focus on in silico estimation of MHC binding affinity and are limited by low positive predictive value for actual peptide presentation, inadequate support for rare MHC alleles, and poor scalability to high-throughput data sets. To address these limitations, we developed MHCnuggets, a deep neural network method to predict peptide-MHC binding. MHCnuggets is the only method to handle binding prediction for common or rare alleles of MHC Class I or II, with a single neural network architecture. Using a long short-term memory network (LSTM), MHCnuggets accepts peptides of variable length and is capable of faster performance than other methods. When compared to methods that integrate binding affinity and HLAp data from mass spectrometry, MHCnuggets yields a fourfold increase in positive predictive value on independent MHC-bound peptide (HLAp) data. We applied MHCnuggets to 26 cancer types in TCGA, processing 52.6 million allele-peptide comparisons in under 2.3 hours, yielding 103,587 candidate immunogenic missense mutations (IMMs). IMM hotspots occurred in 36 genes, including 22 driver genes. Predicted IMM load was significantly associated with increased immune cell infiltration (p&lt;2e-16), including CD8+ T cells. Notably, only 0.15% of predicted immunogenic missense mutations were observed in &gt;2 patients, with 65% of these derived from driver mutations. Our results provide a new method for neoantigen prediction with high performance characteristics and demonstrate its utility in large data sets across human cancers.
Citation Format: Xiaoshan M. Shao, Rohit Bhattacharya, Justin Huang, Ashok Sivakumar, Collin Tokheim, Lily Zheng, Dylan Hirsch, Ben Kaminow, Ashton Omdahl, Maria Bonsack, Angelika B. Riemer, Victor E. Velculescu, Valsamo Anagnostou, Kymberleigh Pagel, Rachel Karchin. High-throughput prediction of MHC Class I and Class II neoantigens with MHCnuggets [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 A33.
Abstract A43: Exploiting off-target effects of estrogen receptor-targeting drugs to sensitize breast cancer to immune killing
Authors: Wolfson Benjamin , Schlom Jeffrey , Hodge James 
Published: March 2020

Abstract
1 in 8 women will be diagnosed with breast cancer within their lifetime. The majority of women are diagnosed with estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), or HER2+ breast cancers. The standard of care for ER+ breast cancer is treatment with selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) drugs. While these are highly effective for ER+ breast cancers and additional targeted drugs exist for PR+ and HER2+ cancers, there are currently no targeted therapeutic strategies for the 10-15% of women who are diagnosed with triple-negative breast cancer (TNBC). We hypothesize that estrogen receptor-targeting drugs are capable of inducing phenotypic changes to sensitize breast tumor cells to immune-mediated killing regardless of their ER status. In this study, we used in vitro killing assays and molecular characterization of ER+ and ER- cell lines to identify that SERM and SERD drugs sensitize breast cancer to killing by healthy-donor natural killer (NK) cells regardless of their ER status. While tamoxifen (SERM) and fulvestrant (SERD) had no cytotoxic or antiproliferative effect on ER- cells, pretreatment with either resulted in increased NK-mediated cell lysis. Through RNAseq analysis of tamoxifen-treated ER+ and ER- cells, we identified increased activation of both apoptotic and death receptor signaling pathways. These pathways play a key role in immunogenic modulation, indicating a potential mechanism for tamoxifen-induced tumor sensitization to immune cell lysis. It has previously been reported that in addition to binding to ER, both tamoxifen and fulvestrant bind to G protein-coupled estrogen receptor 1 (GPR30). We found that GPR30 is expressed in both ER+ and ER- breast cancer cells. Using the specific GPR30 agonist G-1, we demonstrated that targeted activation of GPR30 signaling resulted in increased NK cell killing. These data indicate that the observed ER-independent immunogenic modulation of breast cancer cells may be occurring through GPR30. Together, these findings demonstrate a novel effect of SERM and SERD drugs on the interaction between both ER+ and ER- tumor cells with the immune system. This study is the first to demonstrate the potential use of ER-targeting drugs in immunotherapy combinations in an ER-agnostic manner and may inform novel immunotherapy strategies in breast cancer.
Citation Format: Benjamin Wolfson, Jeffrey Schlom, James Hodge. Exploiting off-target effects of estrogen receptor-targeting drugs to sensitize breast cancer to immune killing [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 A43.
Abstract A48: Inactivation of Fbxw7 impairs dsRNA sensing and confers resistance to PD-1 blockade
Authors: Gstalder Cécile , Liu David , Miao Diana , Devine Alexander , Lutterbach Bart , Pancholi Priya , Shettigar Megha , Buchbinder Elizabeth , Carter Scott , Manos Michael , Rojas-Rudilla Vanesa , Brennick Ryan , Gjini Evisa , Lako Ana , Rodig Scott , Yoon Charles , Freeman Gordon , Hodi F. Stephen , Van Allen Eliezer M. , Haq Rizwan 
Published: March 2020

Abstract
Immunotherapies such as anti-PD-1 antibodies can induce durable responses in a subset of cancer patients, but intrinsic or acquired resistance occurs in most cases. Understanding the molecular mechanisms that drive resistance and response to immunotherapies could therefore lead to alternative treatment strategies exhibiting greater efficacy and precision. To identify new tumor cell-intrinsic mechanisms of resistance to PD-1 blockade, we evaluated metastatic melanoma patients who exhibited complete regression of all but one metastatic site following anti-PD-1 therapy. In one patient, we observed a loss-of-function mutation in the tumor suppressor gene F-Box and WD repeat domain containing 7 (FBXW7)—specifically in the resistant tumor. Using an immunocompetent, anti-PD-1 sensitive melanoma mouse model, we demonstrated that Fbxw7 loss of function in tumor cells causes resistance to PD-1 blockade. We showed that the genetic deletion of Fbxw7 in tumor cells alters the tumor immune microenvironment—including decreased effector cells and increased suppressive cells—in addition to diminished responses to viral sensing and interferon signaling pathways in vivo. Mechanistically, we found that Fbxw7 is necessary for the expression of the dsRNA sensors Mda5 and Rig-I. As a consequence, Fbxw7 is required for dsRNA-induced type I interferon production and interferon signaling in tumor cells. Conversely, restoration of the dsRNA signaling pathway in Fbxw7-deficient cells is sufficient to increase MHC-I expression and to suppress growth of Fbxw7-deficient tumors, thereby promoting antitumor immunity. Our findings establish a hitherto unrecognized role of the tumor suppressor gene FBXW7 in tumor immunity and sensitivity to immunotherapy. Collectively, these findings establish a novel tumor-intrinsic pathway of resistance and suggest that therapeutic reactivation of viral sensing pathways could improve clinical responses to checkpoint inhibitors in genomically defined populations.
Citation Format: Cécile Gstalder, David Liu, Diana Miao, Alexander Devine, Bart Lutterbach, Priya Pancholi, Megha Shettigar, Elizabeth Buchbinder, Scott Carter, Michael Manos, Vanesa Rojas-Rudilla, Ryan Brennick, Evisa Gjini, Ana Lako, Scott Rodig, Charles Yoon, Gordon Freeman, F. Stephen Hodi, Eliezer M. Van Allen, Rizwan Haq. Inactivation of Fbxw7 impairs dsRNA sensing and confers resistance to PD-1 blockade [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 A48.
Abstract A59: Inhibition of Glycogen Synthase Kinase 3 (GSK-3) synergizes with anti-PD-1 by potentiating tumor-infiltrated CD8+ T-cells
Authors: Krueger Janna , Taylor Alison , Kazanova Alexandra , Jeidane Saloua , Motta Vinicius , Watson Ian , Rudd Christopher E. 
Published: March 2020

Abstract
Anti-programmed cell death-1 (anti-PD-1) blockade in tumor therapy results in an expansion of CD8+ T cells and can restore the function of exhausted CD8+ T cells. We identified GSK-3 as a key upstream kinase of regulating PD-1 expression. Inhibition of GSK-3 in CD8+ T cells increased Tbx21 (Tbet), which suppressed Pdcd1 (PD-1) transcription (Taylor et al., Immunity 2016). In controlling spontaneous pulmonary metastasis of B16 melanoma and EL-4 lymphoma cells, GSK-3 blockade is as effective as anti-PD-1 blocking antibody (Taylor et al., Cancer Research 2018). Given the clinical importance in devising strategies to overcome tumor resistance to immune checkpoint blockade, we assessed whether the combined use of GSK-3 small-molecule inhibitor (SMI) and anti-PD-1 can overcome resistance to anti-PD-1 monotherapy. Indeed, GSK-3 SMI and anti-PD-1 synergized in therapy against solid B16 tumors that are resistant to monotherapy, leading to delayed tumor growth. Further, the synergy of GSK-3 SMI and anti-PD-1 therapy has been successfully confirmed by using adoptive transfer of OT1 cells into B16-OVA tumor-bearing mice. High-dimensional profiling of tumor-infiltrated lymphocytes (TILs) using mass cytometry (CyTOF) showed that the combination therapy gave an increase in cellularity of CD8+ effector memory T cells, which correlated to better tumor control. Transcriptome analysis of these CD8+ TILs highlighted the increased cytotoxicity as shown by significant changes of granzymes. Our findings outline a next-generation approach of potentiating PD-1 antibody therapy with SMIs of GSK-3 that synergizes as therapy by boosting the cellularity and cytotoxicity of tumor infiltrated CD8+ T cells.
Citation Format: Janna Krueger, Alison Taylor, Alexandra Kazanova, Saloua Jeidane, Vinicius Motta, Ian Watson, Christopher E. Rudd. Inhibition of Glycogen Synthase Kinase 3 (GSK-3) synergizes with anti-PD-1 by potentiating tumor-infiltrated CD8+ T-cells [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 A59.
Abstract A62: Inhibition of tumor growth by novel CART redirected against cells expressing high levels of fibroblast activation protein
Authors: Noguera-Ortega Estela , Todd Leslie , Monslow James , Sun Jing , Albelda Steven M. , Pure Ellen 
Published: March 2020

Abstract
Cancer-associated fibroblasts (CAFs) support tumor growth and metastasis of virtually all solid tumors, making them a potential “universal therapeutic target.” However, there are challenges to designing CAF targeted therapies. First, CAFs are heterogeneous, consisting of tumor-promoting and tumor-restraining populations. Second, molecular targets expressed strictly by tumor-promoting CAFs have yet to be defined. Nonetheless, Fibroblast Activation Protein (FAP) is selectively overexpressed on tumor-promoting CAFs. Moreover, deleting FAP+ cells inhibits tumor growth in preclinical models due to reductions in stroma-dependent signals that support tumor cell survival, growth, and progression and in stroma-derived immunosuppressive factors and can enhance efficacy of other therapies when given in combination. Prior studies in preclinical models suggest, however, that selective elimination of FAPhigh cells while sparing normal FAP+ cells that typically express lower levels of FAP may be necessary to avoid toxicity due to on-target, off-tumor effects. Thus, the aim of this study was to generate a FAP-chimeric antigen receptor (CAR) that selectively targets FAPhigh cells but that exhibits minimal activity against FAPlow cells for use in future clinical trials. We generated a FAP-CAR containing a scFv based on a monoclonal antibody (mAb) we generated that reacts with human and mouse FAP, the CD8 transmembrane region, and the CD3z and 41BB cytoplasmic domains. We show that primary human T cells transduced with this novel FAP-CAR exhibit strong reactivity against cells expressing high levels of human or mouse FAP but not FAPlow or FAP-negative cells. Moreover, these FAP-CART cells inhibited the growth of human FAP-negative A549 tumor xenografts infiltrated by FAP+ murine CAFs in NSG mice. Based on these characteristics, this novel FAP-CAR will be developed for use in clinical trials for human cancer patients.
Citation Format: Estela Noguera-Ortega, Leslie Todd, James Monslow, Jing Sun, Steven M. Albelda, Ellen Pure. Inhibition of tumor growth by novel CART redirected against cells expressing high levels of fibroblast activation protein [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 A62.
Abstract A66: Intracavity infusions of autologous cellular immunotherapy in the treatment of refractory malignant pleural and ascites: A Chinese population-based cohort study
Authors: Qiao Guoliang 
Published: March 2020

Abstract
Objectives: we have explored the potential efficacy and safety of autologous adoptive T cells represented by dendritic cell (DC)-cytokine-induced killer (CIK) infused within cavity in advanced cancer patients with malignant pleural effusion and ascites.
Methods: The apheresis for collection of peripheral blood mononuclear cells was performed in 37 recruited patients. DC-CIKs were expanded ex vivo until qualified for intracavity perfusions for three consecutive times. The quantitative volume of malignant effusions was recorded by radiologic imaging assay. The clinical adverse reactions were analyzed.
Results: For the quantitative assay for those effusions, 1 patient has achieved complete response, 13 patients have achieved PR, 12 patients have stable diseases, and 11 patients have progressive diseases, respectively, yielding a total clinical control rate of 70.3%. After adjusting for competing risk factors, number of concurrent metastasis distribution of organs (p=0.007) and infused number of CIKs (p=0.013) remained independent factors associated with malignant effusion remission. Further exploration demonstrated that the infused CD3+/CD8+ and CD8+/CD28- T-cell populations were able to determine the clinical responses (P&lt;0.05). Moreover, elevated peripheral blood CD3+/CD8+ and declined CD4+/CD25+ T-cell population were noticed in malignant effusion remission group compared with non-remission group (P &lt;0.05). Fewer adverse reactions were recorded.
Conclusions: We have provided the novel therapeutic approach by autologous cellular immunotherapy with confirmed clinical efficacy and safety in the stably controllable malignant effusions. The intracavity infusions were featured by the immunologic T-cell recovery and clinical remission of those effusions.
Note:This abstract was not presented at the conference.
Citation Format: Guoliang Qiao. Intracavity infusions of autologous cellular immunotherapy in the treatment of refractory malignant pleural and ascites: A Chinese population-based cohort study [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 A66.
Abstract A8: Immuno-phenotyping of tumor-specific CD8 T cells using high-dimensional mass cytometry
Authors: Roumanes David , Fehlings Michael , Yadav Mahesh , Nardin Alessandra 
Published: March 2020

Abstract
There is strong evidence that tumor-specific T cells play a central role in tumor rejection. However, few tools can simultaneously detect rare antigen-specific T cells and deeply characterize their function and phenotype. immunoSCAPE leverages the high-dimensional immune profiling capabilities of mass cytometry combined with a unique technology for the identification of antigen-specific T cells to support the development of immunotherapy strategies. By applying cytometry by time of flight in conjunction with combinatorial peptide-MHC tetramer staining and high-performance dimensional analysis tools, we broadly and sensitively map T-cell reactivity against MHC-class I epitopes while concurrently performing in-depth characterization of these rare antigen-specific T cells. Here, we have applied our unique capabilities to detect and characterize circulating neoantigen-specific T cells in lung carcinoma patients undergoing atezolizumab treatment. Out of 782 neoantigen candidates, T-cell reactivity against 13 unique neoantigens was detected within patients who responded to atezolizumab treatment, while T cells within nonresponder patients recognized 7 neoantigens. Additionally, neoantigen-specific CD8 T cells from treatment responders exhibit a differentiated effector phenotype similar to CMV or EBV-specific T cells, whereas neoantigen-specific CD8 T cells from nonresponders display a memory-like phenotype, suggesting that the properties of tumor-reactive T cells may be associated with clinical response to anti-PD-L1 treatment. By providing insight into the nature and function of tumor-specific T cells, immunoSCAPE’s unique high-dimensional immune profiling platform is a valuable tool to guide the development of novel immunotherapy strategies through assessment of drug biologic activity, definition of mechanism of action, and identification of biomarkers of patient response.
Citation Format: David Roumanes, Michael Fehlings, Mahesh Yadav, Alessandra Nardin. Immuno-phenotyping of tumor-specific CD8 T cells using high-dimensional mass cytometry [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 A8.
Abstract A80: Mapping immune landscape in clear cell renal carcinoma by single-cell genomics
Authors: Vishwakarma Ajaykumar , Bocherding Nick , Chimenti Michael , Vishwakarma Purshottam , Nepple Kenneth , Salem Aliasger , Jenkins Russell W. , Zhang Weizhou , Zakharia Yousef 
Published: March 2020

Abstract
Human clear cell renal cell carcinoma (ccRCC) is one of the most immunologically distinct tumor types due to high levels of tumor-infiltrating immune cells including T cells, yet not every patient responds to immunotherapy. Interestingly, in contrast to other cancers, infiltration with cytotoxic CD8+ T cells is associated with poorer overall survival in ccRCC, suggesting that subpopulations of CD8+ and other immune cells may underlie this observation. To characterize the tumor immune microenvironment of ccRCC, we applied single-cell RNA sequencing along with T-cell receptor sequencing to map the transcriptomic heterogeneity of 25,688 individual CD45+ lymphoid and myeloid cells in matched tumor and blood from patients with ccRCC. We identified multiple and distinct immune cell phenotypes for B and T (CD4 and CD8) lymphocytes, natural kill (NK) cells, and myeloid cells. Evaluation of T-cell receptor (TCR) sequences revealed limited shared clonotypes between patients, whereas tumor-infiltrating T-cell clonotypes were frequently found in peripheral blood, albeit in lower abundance. Evaluation of myeloid subsets revealed unique gene programs defining monocytes, dendritic cells, and tumor-associated macrophages. In summary, here we have leveraged scRNA-seq to refine our understanding of the relative abundance, diversity, and complexity of the immune landscape of ccRCC. This report represents the first such characterization of the ccRCC immune landscape using scRNA-seq. With further characterization and functional validation, these findings may identify novel subpopulations of immune cells amenable to therapeutic intervention.
Citation Format: Ajaykumar Vishwakarma, Nick Bocherding, Michael Chimenti, Purshottam Vishwakarma, Kenneth Nepple, Aliasger Salem, Russell W. Jenkins, Weizhou Zhang, Yousef Zakharia. Mapping immune landscape in clear cell renal carcinoma by single-cell genomics [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 A80.
Abstract A81: Identifying cellular immune components that correlate with response to immunotherapy in breast cancer using murine models
Authors: Mehta Anita K. , Castrillion Jessica A. , Sotayo Alaba , Mittendorf Elizabeth A. , Letai Anthony G. , Guerriero Jennifer L. , Cheney Emily 
Published: March 2020

Abstract
The heterogeneity of the tumor microenvironment may contribute to the lack of durable responses of immunotherapy in breast cancer. To understand factors that contribute to tumor immune cell heterogeneity, we report a detailed analysis and comparison of the immune tumor microenvironment of the autochthonous MMTV-PyMT murine breast cancer model resembling luminal B breast cancer and corresponding syngeneic models. We obtained tumors from MMTV-PyMT mice and used them to generate syngeneic models using either 1E6, 1E5, or 1E4 cells injected into the mammary fat pad of FVB/NJ wild-type mice. When tumors reached 100 mm3, tumors were harvested and quantitative flow-cytometry and NanoString analysis was performed. We have identified that the number of cells inoculated to generate syngeneic tumors significantly influences tumor latency, the tumor immune microenvironment, and the response to immune checkpoint blockade (ICB). Compared to the autochthonous model, the 1E6 and 1E5 model had significantly more tumor-infiltrating lymphocytes (TILs; CD3+, CD4+, and CD8+) and the highest proportion of PD-L1-positive myeloid cells. We found that increased TILs and expression of PD-L1 on myeloid cells were the best predictors of response to PD-L1 or CTLA-4 therapy but that tumor cell expression of PD-L1 and T-cell expression of PD-1 did not correspond to beneficial outcome of treatment. Both the 1E6 and 1E5 models responded to PD-L1 and/or CTLA-4 ICB therapy, whereas the 1E4 and autochthonous models were resistant. These matched sensitive and resistant tumor models represent a unique opportunity to further interrogate the TME in breast cancer.
Citation Format: Anita K. Mehta, Jessica A. Castrillion, Alaba Sotayo, Elizabeth A. Mittendorf, Anthony G. Letai, Jennifer L. Guerriero, Emily Cheney. Identifying cellular immune components that correlate with response to immunotherapy in breast cancer using murine models [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 A81.