bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B21: Dual immunotherapy targeting macrophages and PD-1 immune checkpoint for treatment of melanoma
Authors: Shudde Claire E. , Patel Jalpa , Rajan Robin , Shmeeda Hilary , Nguyen Dung , Gabizon Alberto A. , La-Beck Ninh M. 
Published: March 2020

Abstract
Blockading antibodies against PD-1/PD-L1 immune checkpoints are approved for melanoma treatment; however, only a minority of patients experience durable remission. Our previous work suggested that pegylated liposomal alendronate (PLA) targets tumor-associated macrophages, another mediator of immunosuppression, and polarized them towards an antitumor phenotype. We hypothesized that dual immunotherapy with PLA and PD-1 inhibitor would result in enhanced efficacy by targeting nonoverlapping immune escape mechanisms. In vitro cytotoxicity studies were performed in B16-OVA melanoma and murine bone marrow-derived dendritic cells. In vivo efficacy/toxicity studies were conducted in seven-week old C57BL/6 mice with 100,000 B16-OVA cells implanted on the rear flank. Once tumors were palpable, mice (n=4-5/group) were randomized to receive PLA (alendronate 4 mg/kg) + α-PD-1 mAb (10 mg/kg), vehicle + IgG-isotype, PLA + IgG-isotype, or vehicle + α-PD-1. Tumor growth was monitored, and at endpoint, tissues (tumors, lymph nodes, livers, kidneys, spleen, intestines, and lungs) were harvested for analysis by flow cytometry and histopathology. Neither PLA nor α-PD-1 were cytotoxic to melanoma or dendritic cells in vitro when compared to doxorubicin (cytotoxic chemotherapy). Mice treated with PLA + α-PD-1 had significantly smaller tumors compared to placebo controls (p=0.0015) and α-PD-1 monotherapy (p=0.0168).There were no significant pathologic changes in tissues. Assessment of immune responses in tumors and sentinel lymph nodes is ongoing. Dual immunotherapy targeting tumor-associated macrophages and the PD-1 checkpoint is safe and more efficacious than monotherapies solely targeting the PD-1 checkpoint in the treatment of murine melanoma. This is rapidly translatable to clinical trials, as the separate components are already approved for use in humans.
Citation Format: Claire E. Shudde, Jalpa Patel, Robin Rajan, Hilary Shmeeda, Dung Nguyen, Alberto A. Gabizon, Ninh M. La-Beck. Dual immunotherapy targeting macrophages and PD-1 immune checkpoint for treatment of melanoma [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 B21.
Abstract B24: Using L-fucose to render melanomas immune hot: Roles of melanoma HLA-DRB1 and CD4+T cell-mediated antitumor immunity
Authors: Lester Daniel K. , Mercurio Matt , Innamorato Pasquale , Krithika Kodumudi , Danial Williamson , Gregory Watson , Shari Pilon-Thomas , Jane Messina , Thomas Kerri L. , McCarthy Susan , Markowitz Joseph , Haltiwanger Robert , Lau Eric 
Published: March 2020

Abstract
Responsiveness to immunotherapies is limited in melanoma to subsets of patients. Despite attempts to improve responsiveness to immunotherapies by testing combination therapies, patients often experience significant adverse events that require the termination of treatment. Although causes of nonresponsiveness remain unclear and the subject of active investigation, a commonality among refractory tumors is low pretreatment levels of tumor-infiltrating lymphocytes (TILs). Thus, studies aiming to elucidate the interactions between melanoma and immune cells and to increase TIL levels are anticipated to improve therapies. We previously reported that fucosylation (the post-translational modification of proteins with the dietary plant sugar L-fucose), is altered in melanoma. Increasing fucosylation levels in melanoma—genetically or with oral L-fucose—suppresses tumor growth, metastasis, and increases TILs in immune competent mouse models of melanoma (Lau et al., 2015). The mechanisms underlying how melanoma fucosylation appears to trigger antitumor immunity are unclear. Here, we identified TIL subpopulations triggered by fucosylation to mediate tumor suppression and a key molecular mechanism. In NRAS- and BRAF-mutant melanoma models, dietary L-fucose suppressed tumor growth by ~50-60% and increased TILs by ~10-50-fold. Of all TIL subpopulations examined, CD3+ T cells were most increased by L-fucose, doubling or increasing by 15-fold, in NRAS- or BRAF-mutant models, respectively. Depletion of CD4+ T cells abrogated L-fucose-triggered TIL increases and tumor suppression, indicating that CD4+ T cells are central for antitumor immune effects of L-fucose. We identified the Class II MHC protein HLA-DRB1 as expressed and fucosylated in melanoma cells and confirmed its requirement for L-fucose-triggered, CD4+ T cell-dependent tumor suppression in vivo. Roles of HLA-DRB1 fucosylation in melanoma, effects on CD4+ T cell biology, and how L-fucose can enhance immunotherapies will be discussed. Our studies highlight how L-fucose supplementation can render tumors “immune hot” and represents a potential therapeutic strategy for improving immunotherapies.
Citation Format: Daniel K. Lester, Matt Mercurio, Pasquale Innamorato, Kodumudi Krithika, Williamson Danial, Watson Gregory, Pilon-Thomas Shari, Messina Jane, Kerri L. Thomas, Susan McCarthy, Joseph Markowitz, Robert Haltiwanger, Eric Lau. Using L-fucose to render melanomas immune hot: Roles of melanoma HLA-DRB1 and CD4+T cell-mediated 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 B24.
Abstract B28: ERAP2 overexpression is a marker for reduced anti-PD-1 response in nasopharyngeal carcinoma
Authors: Tay Joshua K. , Ma Brigette B.Y. , Varma Sushama , Lim Yaw Chyn , Tan Chee Seng , Lo Kwok Wai , Sunwoo John B. , Cullen Kevin J. , Goh Boon Cher , West Robert B. 
Published: March 2020

Abstract
Nasopharyngeal carcinoma (NPC) is an EBV-associated epithelial cancer common in the Southern Chinese population. Patients with recurrent or metastatic NPC treated with PD-1 blockade showed a response rate of 20.5%, with no correlation observed between the expression of PD-L1 and treatment response. In an effort to identify biomarkers for anti-PD-1 treatment response, we evaluated a cohort of 10 NPC patients with recurrent or metastatic NPC treated with nivolumab or pembrolizumab. Laser capture microdissection was performed on pretreatment biopsies, with tumor and microenvironment compartments separately microdissected. Nasopharyngeal epithelium from normal nasopharyngeal biopsies were also microdissected as controls. Smart-3SEQ, a novel 3´ end RNA-Seq technique that allows for the accurate quantification of transcript abundance in FFPE samples, was performed to obtain gene expression libraries. ERAP2, a zinc metalloaminopeptidase that performs N-terminal trimming of antigenic epitopes for presentation by MHC class I, was among the most highly upregulated genes in the tumor compartment of nonresponders (adjusted p = 0.033). ERAP2 overexpression was also observed in NPC tumors compared to normal controls. Immunohistochemistry validated the overexpression of ERAP2 in nonresponders, while responders had similar expression to normal controls. In conclusion, ERAP2 is overexpressed in NPC tumors and is a promising biomarker for reduced anti-PD-1 response in NPC.
Citation Format: Joshua K. Tay, Brigette B.Y. Ma, Sushama Varma, Yaw Chyn Lim, Chee Seng Tan, Kwok Wai Lo, John B. Sunwoo, Kevin J. Cullen, Boon Cher Goh, Robert B. West. ERAP2 overexpression is a marker for reduced anti-PD-1 response in nasopharyngeal carcinoma [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 B28.
Abstract B3: Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy
Authors: Zhang Yan , Du Xuexiang , Liu Mingyue , Tang Fei , Zhang Peng , Ai Chunxia , Fields James K. , Sundberg Eric J. , Latinovic Olga S. , Devenport Martin , Zheng Pan , Liu Yang 
Published: March 2020

Abstract
It remains unclear why the clinically used anti-CTLA-4 antibodies, popularly called checkpoint inhibitors, have severe immunotherapy-related adverse effects (irAEs) and yet suboptimal cancer immunotherapeutic effects (CITE). Here we report that while irAE-prone Ipilimumab and TremeIgG1 rapidly direct cell surface CTLA-4 for lysosomal degradation, the non-irAE-prone antibodies we generated, HL12 or HL32, dissociate from CTLA-4 after endocytosis and allow CTLA-4 recycling to cell surface by the LRBA-dependent mechanism. Disrupting CTLA-4 recycling results in robust CTLA-4 downregulation by all anti-CTLA-4 antibodies and confers toxicity to a non-irAE-prone anti-CTLA-4 mAb. Conversely, increasing the pH sensitivity of TremeIgG1 by introducing designed tyrosine-to-histidine mutations prevents antibody-triggered lysosomal CTLA-4 downregulation and dramatically attenuates irAE. Surprisingly, by avoiding CTLA-4 downregulation and due to their increased bioavailability, pH-sensitive anti-CTLA-4 antibodies are more effective in intratumor regulatory T-cell depletion and rejection of large established tumors. Our data establish a new paradigm for cancer research that allows for abrogating irAE while increasing CITE of anti-CTLA-4 antibodies.
Citation Format: Yan Zhang, Xuexiang Du, Mingyue Liu, Fei Tang, Peng Zhang, Chunxia Ai, James K. Fields, Eric J. Sundberg, Olga S. Latinovic, Martin Devenport, Pan Zheng, Yang Liu. Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy [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 B3.
Abstract B32: Metformin reduces PD-L1 expression in the tumor and enhances the efficacy of vaccine-generated CD8 T cells in a murine model of triple-negative breast cancer
Authors: Munoz Luis E. , Bommireddy Ramireddy , Huang Haley L. , Pack Christopher D. , Ramachandiran Sampath , Selvaraj Periasamy 
Published: March 2020

Abstract
Immunotherapy has emerged as a promising treatment of breast cancer; however, response rates to therapy remain far from ideal. We have developed a new platform for personalized vaccine immunotherapy that utilizes tumor tissue to generate tumor membrane vesicles (TMVs). These TMVs can be incorporated with immunostimulatory molecules such as IL-12 and B7-1 and used for immunization. In this study, we investigated the combinatorial effect of TMV-based vaccine immunotherapy, to induce an antitumor immune response, with the type 2 diabetes drug metformin, which has been reported to exert antitumor effects by promoting CD8 T-cell activity in the tumor microenvironment. Our results show that TMV vaccination inhibits primary tumor growth in preclinical tumor models, while the combination with metformin resulted in greater inhibition of primary growth. TMV vaccination reduced the metastatic burden in the lungs while the combination with metformin further abrogated metastatic spread. Interestingly, TMV vaccination alone induced a significant increase in T-cell infiltration to the tumor, and combination with metformin caused a decrease in the accumulation of T cells, despite having better control of tumor growth. Further, we show that metformin can reduce PD-L1 expression within the tumor microenvironment and result in more IFN-γ-producing CD8 T cells within the tumor, providing a mechanistic insight for the improvement of TMV-based vaccine immunotherapy.
Citation Format: Luis E. Munoz, Ramireddy Bommireddy, Haley L. Huang, Christopher D. Pack, Sampath Ramachandiran, Periasamy Selvaraj. Metformin reduces PD-L1 expression in the tumor and enhances the efficacy of vaccine-generated CD8 T cells in a murine model of triple-negative breast 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 B32.
Abstract B35: Epitope-binding promiscuity of HLA class I molecules shapes the efficacy of checkpoint blockade immunotherapy
Authors: Manczinger Máté , Balogh Gergő , Koncz Balázs , Kemény Lajos , Papp Balázs , Pál Csaba 
Published: March 2020

Abstract
Immune checkpoint inhibitors (ICI), which target inhibitory receptors on T cells and thereby promote antitumor immune responses, have achieved considerable success in clinical care against a range of cancer types. However, only a subset of patients responds adequately to ICI-based immunotherapies. Therefore, it is of utmost importance to understand the immunologic mechanisms underlying resistance and adverse effects. It has been previously shown that certain MHC class I molecules are capable of promiscuous peptide binding, as they are associated with a much wider range of epitopes than others. The functional implications of such an elevated epitope-binding repertoire on the efficacy of cancer immunotherapy are unknown. In this work, we examine HLA genotypes of individuals receiving checkpoint blockade immunotherapy using two published cohorts. We demonstrate that cancer patients carrying HLA class I alleles with promiscuous peptide binding display significantly worse prognosis after ICI immunotherapy. This association remains significant after controlling for tumor types, mutational burden, and HLA genetic diversity. We also found that cancer samples of patients carrying highly promiscuous HLA class I alleles display significantly reduced expression of PD1 and CTLA-4 receptors, important markers of T-cell activation in the tumor microenvironment. Moreover, such promiscuous HLA alleles bind neoepitopes with reduced affinity. These findings indicate that high promiscuity is suboptimal due to a reduced specificity of epitope binding, yielding inadequate antitumor immune response.
Citation Format: Máté Manczinger, Gergő Balogh, Balázs Koncz, Lajos Kemény, Balázs Papp, Csaba Pál. Epitope-binding promiscuity of HLA class I molecules shapes the efficacy of checkpoint blockade immunotherapy [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 B35.
Abstract B39: The T-cell repertoire as a biomarker for response to anti PD-1 immunotherapy
Authors: Philip Hagit , Snir Tom , Gordin Miri , Wigelman Yoav , Zilberberg Alona , Efroni Sol 
Published: March 2020

Abstract
The prediction of patients’ response to checkpoint immunotherapy is currently imprecise. Here, we show that a measurement of the T-cell repertoire, from peripheral blood of mice, is enough to predict which mice would or would not respond to anti-PD1 treatment. To show this, we used a syngeneic orthotopically implanted CL261 glioma-bearing mouse model. We followed the mice over the timeline of tumor implantation and checkpoint immunotherapy, with blood samples on days 0, 7, 21, 35, 49, and 63. Since the (syngeneic) implanted tumor is bioluminescent, we were able to monitor tumor size using bioluminescence imaging (up to 9 measures, 1 measure per week), up to day 63 post-tumor inoculation. We then produced more than 130 T-cell receptor libraries for the alpha and beta chains and sequenced these libraries to produce a data set of the dynamics of the T-cell repertoire during tumor progression and during response to treatment. In this model, only 30% of animals respond to treatment, which allowed us to look at the repertoires of two distinct groups: responders and nonresponders. Using machine learning, we were able to build a model that allows us to tag, in a validation set, responders and nonresponders, thereby predicting response.
Citation Format: Hagit Philip, Tom Snir, Miri Gordin, Yoav Wigelman, Alona Zilberberg, Sol Efroni. The T-cell repertoire as a biomarker for response to anti PD-1 immunotherapy [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 B39.
Abstract B4: High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model
Authors: Luchtel Rebecca , Bhagat Tushar , Pradhan Kith , Jacobs William , Levine Mark , Verma Amit , Shenoy Niraj 
Published: March 2020

Abstract
Major efforts are under way to identify agents that can potentiate effects of immune checkpoint inhibition. Ascorbic acid (AA) has been previously shown to cause DNA demethylation and corresponding increase in hydroxymethylation in multiple malignancies by enhancing the activity of the Ten-Eleven Translocation (TET) enzymes (Shenoy et al., BCJ 2017; Shenoy et al., JCI 2019; Cimmino et al., Cancer Cell 2017; Agathocleous et al., Nature 2017). Furthermore, AA has re-emerged as a promising anticancer agent based on recent knowledge of pharmacokinetics, discovery of unexpected mechanisms of action, and early phase trials with IV AA (Shenoy et al., Cancer Cell 2018). Here, we report that AA treatment caused genome-wide demethylation and enhanced expression of endogenous retroviral elements in lymphoma cells. AA also increased 5-hydroxymethylcytosine (5hmC) levels of CD8+ T cells and enhanced their cytotoxic activity in a lymphoma coculture system. High-dose AA treatment synergized with anti-PD1 therapy in a syngeneic lymphoma mouse model, resulting in marked inhibition of tumor growth compared with either agent alone. Analysis of the intratumoral epigenome revealed increased 5hmC with AA treatment, consistent with in vitro findings. Analysis of the tumor immune microenvironment revealed that AA strikingly increased intratumoral infiltration of CD8+ T cells and macrophages, suggesting enhanced tumor immune recognition. The combination treatment markedly enhanced intratumoral infiltration of macrophages and CD8+ T lymphocytes, granzyme B production by cytotoxic cells (cytotoxic T cells and natural killer cells), and IL-12 production by antigen-presenting cells compared with single-agent anti-PD1. These data strongly indicate that AA potentiates anti-PD1 checkpoint inhibition through synergistic mechanisms. The study provides a compelling rationale for testing combinations of AA and anti-PD1 agents in lymphoma patients as well as in preclinical models of other malignancies.
Citation Format: Rebecca Luchtel, Tushar Bhagat, Kith Pradhan, William Jacobs, Mark Levine, Amit Verma, Niraj Shenoy. High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model [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 B4.
Abstract B40: The phosphorylation by activated-AMPK induces ERAD of PD-L1 through abnormal glycosylation
Authors: Cha Jong-ho , Yang Wen-Hao , Hong Soon-Sun , Hung Mien-Chie 
Published: March 2020

Abstract
Programmed death ligand-1 (PD-L1) is a major immune checkpoint molecule that enables cancer immune evasion in various cancer types, and therefore the PD-L1/PD-1 axis has been a major target for current cancer immune checkpoint blockade (ICB). However, the regulatory mechanisms of PD-L1 expression are largely undefined. Here, we demonstrate that AMP-activated protein kinase (AMPK) phosphorylates Serine 195 of PD-L1, which induces the ER-associated degradation (ERAD) of PD-L1 via abnormal glycosylation. Further, we identified HRD1 as an ERAD E3 ligase of PD-L1. Ser195-p recruits HRD1 into PD-L1-ERAD complex and finally induces proteasomal degradation of PD-L1 through poly-ubiquitination. This study broadens our understanding of the regulation of PD-L1 expression and has the potential to improve the efficacy of ICB targeting PD-L1/PD-1 and overcome resistance to the ICB.
Citation Format: Jong-ho Cha, Wen-Hao Yang, Soon-Sun Hong, Mien-Chie Hung. The phosphorylation by activated-AMPK induces ERAD of PD-L1 through abnormal glycosylation [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 B40.
Abstract B43: Simultaneous inhibition of CXCR1/CXCR2, TGF-β, and PD-L1 overcomes immune resistance driven by tumor plasticity
Authors: Horn Lucas A. , Riskin Jeffrey , Hempel Heidi A. , Lind Hanne , Fousek Kristen , Hamilton Duane H. , McCampbell Kristen K. , Schlom Jeffrey , Palena Claudia 
Published: March 2020

Abstract
The occurrence of phenotypic plasticity in carcinomas, which results in the acquisition of mesenchymal features by epithelial cancer cells, associates with a poor prognosis and has been described as a mechanism of primary resistance and failure to treatment with checkpoint blockade immunotherapy targeting the PD-1/PD-L1 pathway. IL-8 and TGF-β are two of the factors that mediate phenotypic plasticity in epithelial tumors to promote an immune-suppressive microenvironment. Here we report on an immunotherapy approach aimed at overcoming escape mechanisms mediated by IL-8 and TGF-β accumulation in the tumor microenvironment via the use of two clinical-stage agents: SX-682, a dual CXCR1/2 small-molecule inhibitor, with the bifunctional anti-PD-L1/TGFβRII agent, bintrafusp alfa (M7824) that simultaneously blocks PD-L1 while trapping soluble TGF-β. We demonstrate that the concurrent inhibitions of CXCR1/CXCR2, TGF-β, and PD-L1 signaling synergize to reduce mesenchymal tumor features in murine models of breast and lung cancer, and to markedly increase expression of tumor epithelial E-cadherin while reducing infiltration with suppressive granulocytic myeloid-derived suppressor cells (G-MDSC), significantly enhancing CD4+ and CD8+ T-cell infiltration and activation in tumors, and leading to improved antitumor activity. This combination approach was effective in tumor models with varying immune cell infiltrates, degrees of plasticity, and responses to immunotherapy. The results of these studies provide the rationale for the future evaluation of this multimodal therapy in the clinic.
Citation Format: Lucas A. Horn, Jeffrey Riskin, Heidi A. Hempel, Hanne Lind, Kristen Fousek, Duane H. Hamilton, Kristen K. McCampbell, Jeffrey Schlom, Claudia Palena. Simultaneous inhibition of CXCR1/CXCR2, TGF-β, and PD-L1 overcomes immune resistance driven by tumor plasticity [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 B43.