bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B181: Adenovirus, Semliki Forest virus and vaccinia virus-induced immunogenic cell death augments oncolytic virus immunotherapy
Authors: Ramachandran Mohanraj , Essand Magnus 
Published: February 2019

Abstract
Oncolytic viruses represent new immunotherapy agents with therapeutic effects consisting of direct oncolysis of cancer cells and anticancer immune responses induced upon oncolysis. However, the exact pathways of cell death and the subsequent immune response initiations after oncolysis are not fully elucidated. We have examined the cell death pathways and immune-stimulatory pathways involved in adenovirus (Ad), Semliki Forest virus (SFV) and vaccinia virus (VV) infection. The three viruses activate distinct but different pathways but all of them induced immunogenic cell death (ICD), which is depicted by elevated cell surface exposure of calreticulin (CRT) and extracellular secretion of ATP. Oncolysis-mediated ICD grants dying cells to be phagocytosed and it promotes DC maturation and activation with a Th1-polarized cytokine secretion profile. As a proof of concept, we validated that when DCs are incubated with Ad- or SFV-, but not VV-infected tumor cells expressing a surrogate antigen (CMVpp65), they can efficiently process and cross-present peptides of this antigen to CD8+ T-cells, as shown by specific IFN-γ production. Mice immunized with SFV- or VV-infected murine glioblastoma cells (GL261) elicit a strong and specific T-cell response against GL261. This adaptive immune response can control tumor growth and prolong mice survival after GL261 rechallenge.
Citation Format: Mohanraj Ramachandran, Magnus Essand. Adenovirus, Semliki Forest virus and vaccinia virus-induced immunogenic cell death augments oncolytic virus 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 B181.
Abstract B186: Tumor cell-derived proteases contribute to antigen processing and enhance cross-presentation
Authors: Shields Nicholas J. , Young Katie A. , Jackson Christopher , Young Sarah L. 
Published: February 2019

Abstract
Tumor lysates (TLs) offer a source of both undefined tumor antigens and endogenous adjuvants, called danger-associated molecular patterns (DAMPs), to induce antitumor immune responses. TLs can therefore serve clinical applications for immunotherapy, including vaccination and as a platform for the expansion for tumor-specific T-cells for use in adoptive cell therapy. TL-based approaches offer the advantage of inducing antitumor immunity without the need to identify specific tumor antigens, a major challenge limiting the clinical application of immunotherapies for solid tumors. Immunogenic cell death (ICD) in tumor cells has proven crucial for the generation of robust antitumor immune responses, suggesting that the induction of ICD may improve the efficacy of TL-based immunotherapies. Here, we examined the immunogenicity of TLs prepared from tumor cells exposed to increasing levels of heat (37°C, 42°C and 56°C), using the MC38-OVA/OT-I system. Molecular correlates of ICD were assessed during the course of heat-treatment and in TL preparations. Notably, lethal heat-treatment (56°C) induced primary necrosis with concomitant caspase activation, calreticulin exposure, HMGB1 release and HSP upregulation. All TLs promoted maturation of bone marrow-derived dendritic cells (BMDC), as evidenced by CD80 and CD86 upregulation, and elicited protective antitumor immunity in vaccinated mice. However, only TLs prepared from lethal heat-treated tumor cells promoted cross-presentation in BMDC to elicit antigen-specific T-cell activation ex vivo. Marked proteolytic activity was observed in lethal heat-treated tumor cells, which were capable of processing antigen and binding resultant peptides. Interestingly, inhibition of broad protease activity in lethal heat-treated TLs markedly reduced cross-presentation. Selective inhibition of calpains, but not caspases, cathepsins or the proteasome, reduced antigen processing by heat-killed tumor cells.Together, this demonstrates that tumor-derived proteases can contribute to antigen processing and enhance cross-presentation. Our data suggest that in addition to DAMP release, antigenic processing by proteases in dying tumor cells can influence the immunogenicity of cell death.
Citation Format: Nicholas J. Shields, Katie A. Young, Christopher Jackson, Sarah L. Young. Tumor cell-derived proteases contribute to antigen processing and enhance cross-presentation [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 B186.
Abstract B195: Chemical probes for exploring muropeptide-pattern recognition receptor interactions in cells
Authors: Wang Yen-Chih 
Published: February 2019

Abstract
Peptidoglycan fragments from the bacterial cell wall activate innate immune signaling pathways and limits infections in animals. Indeed, recent studies from the Hang and Mucida laboratories have shown that E. faecium secreted peptidoglycan hydrolase (SagA) generates smaller peptidoglycan fragments, muropeptides, which can enhance host epithelial barrier integrity and enteric pathogen tolerance. However, the direct biochemical interactions of muropeptides with their proposed pattern recognition receptors have been challenging to characterize. Here, I report the chemical synthesis of photoaffinity probes for the analysis of muropeptide-pattern recognition receptor interactions in cells. These studies reveal direct biochemical interactions of muropeptide with pattern recognition receptors and other potential cofactors in mammalian cells. Further characterization of muropeptide-pattern recognition receptor and cofactor complexes will be important for elucidating fundamental mechanisms of innate immunity and inflammation-associated diseases and cancer.
Citation Format: Yen-Chih Wang. Chemical probes for exploring muropeptide-pattern recognition receptor interactions in cells [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B195.
Abstract IA14: Cell transfer immunotherapy targeting unique somatic mutations in cancer
Authors: Rosenberg Steven A. 
Published: February 2019

Abstract
Adoptive cell transfer (ACT) immunotherapy using T lymphocytes with antitumor activity is a living therapy that can be highly effective in patients with a variety of metastatic cancers. Naturally occurring tumor infiltrating lymphocytes (TIL) expanded in vitro and administered following a lymphodepleting preparative regimen mediated objective regression of metastatic melanoma in 55% of 194 patients including complete regressions in 24% of patients who remain ongoing disease-free 3 to 10 years later. To determine the antigens recognized by TIL we developed an approach based on deep exomic sequencing of the cancer and immunologic testing of TIL or peripheral lymphocytes to generate T-cells that recognized immunogenic mutations. TIL from 22 patients with metastatic melanoma recognized 54 random somatic mutations none of which were shared among different melanomas. We next extended these studies to patients with common epithelial cancers and showed that 81 of 99 (82%) patients with a variety human cancer types including esophageal, colorectal, bile duct, gastric, pancreatic, ovarian, cervical and lung cancer contained T-cells that recognized 197 neoantigens all of which were unique except for KRAS (2 patients). Targeting unique cancer mutations has extended the reach of ACT immunotherapy and was used to mediate objective regressions in selected patients with chemorefractory metastatic cancers of the bile duct, colon, cervix, and breast. In addition to the use of naturally occurring mutation-reactive cells, we have genetically engineered autologous lymphocytes to express shared antitumor T- cell receptors (TCR) or chimeric antigen receptors (CAR) for use in ACT immunotherapy that can mediate durable cancer regressions in heavily pretreated patients with refractory lymphomas, sarcomas and melanoma. Autologous T- cells can be used to provide a highly personalized immunotherapy for cancer patients refractory to conventional cancer treatments.
Citation Format: Steven A. Rosenberg. Cell transfer immunotherapy targeting unique somatic mutations in cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA14.
Abstract IA31: Measuring the emergence of non-self in tumors
Authors: Luksza Marta , Solovyov Alexander , Vabret Nicolas , Balachandran Vinod , Riaz Nadeem , Makarov Vladimir , Hellmann Matthew D. , Snyder Alexandra , Funt Samuel , Remark Romain , Merad Miriam , Gnjatic Sacha , Bajorin Dean F. , Rosenberg Jonathan , Leach Steven , Levine Arnold J. , Chan Timothy A. , Bhardwaj Nina , Wolchock Jedd , Greenbaum Benjamin D. 
Published: February 2019

Abstract
Molecules generated by mutational and epigenetic processes in tumors have been associated with recognition of tumors by the innate and adaptive immune system. For example, neoantigens have been implicated in response to checkpoint blockade therapies. Likewise, the display of pathogen-associated patterns by nucleic acids unsilenced by epigenetic alterations have been implicated in activation of the innate immune system. Here we determine molecular features which place a tumor at a selective advantage or disadvantage, and how these selective pressures depend on the tumor’s environment. We have proposed general frameworks to address these questions. In the case of tumor neoantigens, we present a fitness model of candidate immunogenic neoantigens distributed across a tumor’s subclonal structure in a given microenvironment. We show how our approach can be used to characterize response to checkpoint-blockade therapies and apply it to the general problem of immune-driven tumor evolution in a unique cohort of long-term survivors of pancreatic cancer. In the case of immunostimulatory RNA, we proposed a method of calculating entropic forces for determining the likelihood of tumoral RNA being recognized as pathogen-associated and characterizing classes of pathogen mimicry.
Citation Format: Marta Luksza, Alexander Solovyov, Nicolas Vabret, Vinod Balachandran, Nadeem Riaz, Vladimir Makarov, Matthew D. Hellmann , Alexandra Snyder, Samuel Funt, Romain Remark, Miriam Merad, Sacha Gnjatic, Dean F. Bajorin, Jonathan Rosenberg, Steven Leach, Arnold J. Levine, Timothy A. Chan, Nina Bhardwaj, Jedd Wolchock, Benjamin D. Greenbaum. Measuring the emergence of non-self in tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA31.
Abstract A12: Identification of resistance to immune checkpoint blockade
Authors: Gu Shengqing Stanley Gu , Li Ziyi , Bu Xia , Xing Xiaofang , Freeman Gordon , Brown Myles , Liu Xiaole Shirley 
Published: February 2019

Abstract
Despite its enormous success in treating several types of cancer, including melanoma, lung cancer, renal cancer, bladder cancer, and Hodgkin’s lymphoma, immunotherapy still only induces responses in a subset of patients. Understanding the response and resistance mechanisms are still open questions. Based on the reported heterogeneous response to targeted therapies in multiple cell lines, we hypothesize that significant heterogeneity might also exist regarding the response to immune checkpoint blockade (ICB), which may manifest the mechanisms of response/resistance to ICB. To this end, we applied the ClonTracer barcoding system to assess the heterogeneity of response to anti-PD1 and anti-CTLA4 in CT26 colorectal cancer model. Surprisingly, whereas significant heterogeneity exists in the cell line’s ability to initiate cancer in vivo, ICB treatment did not lead to dramatic clonal enrichment compared to control treatment. Therefore, the tumor microenvironment and/or the epigenetic programs in cancer cells may dictate the response to ICB.
Note: This abstract was not presented at the conference.
Citation Format: Shengqing Stanley Gu Gu, Ziyi Li, Xia Bu, Xiaofang Xing, Gordon Freeman, Myles Brown, Xiaole Shirley Liu. Identification of resistance to immune checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A12.
Abstract A73: Optogenetic regulation of T cell metabolism in the tumor microenvironment
Authors: Amitrano Andrea , Walling Brandon , Kim Kyun Do , Berry Brandon , Trewin Adam , Wojtovich Andrew , Kim Minsoo 
Published: February 2019

Abstract
The tumor microenvironment presents significant metabolic challenges to T cells by depleting oxygen and glucose, as well as limiting the uptake of key nutrients. Therefore, T cells and tumor cells engage in fierce metabolic competition, as the demand for both oxygen and glucose in the niche is extremely high. The transition from a resting naïve T cell into an activated and highly proliferative effector T cell requires substantial metabolic reprogramming from relying primarily on oxidative phosphorylation (OxPhos) to the rapid induction of aerobic glycolysis. However, evidence suggests that tumor infiltrating CD8+ T cells show defects in glycolytic functions. In addition, our data indicates that actively migrating effector CD8+ T cells have greater levels of OxPhos activity than stationary cells, imposing an increasing demand for oxygen during T cell migration to the tumor site. To overcome the glycolytic deficiency of the tumor-targeting T cells and boost anti-tumor effector functions at the tumor microenvironment, we developed a genetically encoded light-activated proton pump (fungal proton pump, “Mac”), namely photoactivatable OxPhos (PA-OxPhos) that is expressed in the inner mitochondrial membrane. During OxPhos, electrons enter the electron transport chain (ETC), causing protons to be pumped across the inner mitochondrial membrane to establish a proton gradient. The gradient is then used to generate ATP through complex V (CxV). Therefore, the outward proton pumping through the inner mitochondrial membrane by light stimulation of PA-OxPhos mimics the ETC function and boosts ATP generation in T cells, even in the presence of low levels of oxygen and substrates, giving T cells a metabolic competitive advantage in the tumor microenvironment. PA-OxPhos is tagged with GFP and is expressed in the mitochondria of transfected 293T cells and in activated mouse CD8+ T cells. When cells were treated with Rotenone (an inhibitor of complex I of the ETC), ATP production was decreased after 90 minutes. Importantly, light stimulation of 293T cells expressing PA-OxPhos successfully increased ATP production even in the presence of Rotenone. Our data suggests that PA-OxPhos can remotely provide a competitive metabolic advantage and boost T cell functions in the tumor microenvironment. The utilization of an alternative mechanism for ATP production in T cells could potentially dissipate the failures of T-cell-based cancer immunotherapies in destroying malignant cells of solid tumors.
Citation Format: Andrea Amitrano, Brandon Walling, Kyun Do Kim, Brandon Berry, Adam Trewin, Andrew Wojtovich, Minsoo Kim. Optogenetic regulation of T cell metabolism in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A73.
Abstract B24: Digital signatures of T cell dysfunction predict immunotherapy response
Authors: Jiang Peng 
Published: February 2019

Abstract
Despite success in treating several cancer types, immunotherapy only shows response in a subset of patients. Predicting immunotherapy response and understanding the resistance mechanisms are still open questions. We present a computational framework, Tumor Immune Dysfunction and Exclusion (TIDE), which utilizes the vast amount of public clinical datasets to identify biomarkers of immunotherapy response. TIDE utilized the interaction test in multivariate model to identify the molecular features of tumors where high CD8 T cell infiltration does not associate with survival benefits. The top scored genes are enriched with drivers of T cell dysfunction identified by shRNA screen in mouse models, markers of T cell exhaustion in irreversible state, and reversely correlated with transcriptome profiles of cell types that drives T cell exclusion in tumors. The TIDE signatures from clinical data without immunotherapies can reliably predict the response to both anti-PD1 and anti-CTLA4 therapies in melanoma using pretreatment tumor profiles, with higher accuracy than mutation load, PDL1 expression level, and other biomarkers.
Citation Format: Peng Jiang. Digital signatures of T cell dysfunction predict immunotherapy response [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B24.
Abstract B29: Multiplex three-dimensional optical mapping of tumor immune microenvironment
Authors: Lee Steve Seung-Young , Bindokas Vytautas , Kron Stephen 
Published: February 2019

Abstract
Recent advances in optical tissue clearing and microscopic imaging have facilitated three-dimensional (3D) visualization of large tissues and whole organs at a high resolution. However, to expand its applications to oncology, current challenges such as slow and complicated tissue clearing and uneven immunostaining must be addressed. Here we describe transparent tissue tomography (T3), a tool for rapid, three-dimensional, multiplex immunofluorescence tumor imaging. Cutting tumors into 400 μm macrosections enables simple and rapid immunofluorescence staining, optical clearing, and confocal microscope imaging. Registering and fusing macrosection images yields high resolution 3D maps of multiple tumor microenvironment components and biomarkers throughout a tumor. The 3D maps can be quantitatively evaluated by automated image analysis. As an application of T3, 3D mapping and analysis revealed a heterogeneous programmed death-ligand 1 (PD-L1) distribution in transgenic mouse mammary tumors, with high expression limited to Her2+ tumor cells at the periphery and to CD31+ vascular endothelium in the core. Also, strong spatial correlation between CD45+ immune cell distribution and PD-L1 expression at the tumor margin was determined by T3 analysis of the whole tumors. We also evaluate anti-tumor immune responses after PD-L1 blockade therapy using T3. We observe broad distribution of tumor infiltrating CD3+CD8+ cytotoxic T cells in 3D tumor section following combination therapy of radiation and anti-PD-L1 antibody compared to PBS, anti-PD-L1 antibody alone, or radiation alone treatment group. Moreover, we apply T3 to immunolocalization of cytotoxic lymphocytes in whole core needle biopsies obtained from mouse mammary tumors and human head & neck tumors. We spatially and quantitatively map granzymeB-producing CD3+CD8+ cytotoxic T cells and CD49b+CD31+ natural killer cells in pre-treatment and in-treatment core needle biopsies at cellular resolution and in three dimensions. Meanwhile, T3 analysis is nondestructive, allowing secondary analysis by chromogenic immunohistochemistry (IHC). We anticipate that T3 can be applied broadly to facilitate preclinical studies of tumor immunology and immunotherapy and also find use in spatial, multiparameter analysis of patient biopsies, particularly to improve predictive testing and analysis of immune responses to tumor immunotherapy.
Citation Format: Steve Seung-Young Lee, Vytautas Bindokas, Stephen Kron. Multiplex three-dimensional optical mapping of tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B29.
Abstract B35: Class IIa HDAC inhibition promotes an antitumor macrophage phenotype that induces breast tumor regression and inhibits metastasis
Authors: Guerriero Jennifer L. , Sotayo Alaba , Ponichtera Holly E. , Castrillon Jessica A. , Pourzia Alexandra L. , Schad Sara , Johnson Shawn F. , Carrasco Ruben D. , Lazo Susan B. , Bronson Roderick T. , Davis Scott P. , Lobera Mercedes X. , Nolan Michael A. , Letai Anthony 
Published: February 2019

Abstract
Tumor macrophages generally promote tumorigenesis and are associated with increased vascular density, resistance to chemotherapy and a worse clinical outcome in the majority of human tumors. Therefore, significant pharmaceutical effort has focused on inhibiting the immunosuppressive effects of tumor macrophages by depleting or inhibiting them. However, macrophage types also exist that can promote tumor clearance. Shifting tumor macrophages to an anti-tumor phenotype offers great hope given their plasticity and high numbers in a variety of solid tumors. We recently reported that a novel, first in class, specific class IIa HDAC inhibitor, TMP195, significantly alters the gene expression signature of human monocytes and promotes their polarization to an anti-tumor phenotype in vitro. Here, we demonstrate that a first in class, class IIa histone deacetylase (HDAC) inhibitor, TMP195, can activate tumor macrophages in vivo to induce tumor regression and inhibit pulmonary metastases in a mouse model of breast cancer. We find that TMP195 induces macrophage recruitment and differentiation of highly phagocytic cells within the tumor, which increases tumor cell death while decreasing angiogenesis. Strikingly, we find that TMP195 enhances chemotherapy and immunotherapy to induce durable tumor reduction. These data reveal a novel role for harnessing the anti-tumor potential of macrophages to enhance cancer therapy.
Citation Format: Jennifer L. Guerriero, Alaba Sotayo, Holly E. Ponichtera, Jessica A. Castrillon, Alexandra L. Pourzia, Sara Schad, Shawn F. Johnson, Ruben D. Carrasco, Susan B. Lazo, Roderick T. Bronson, Scott P. Davis, Mercedes X. Lobera, Michael A. Nolan, Anthony Letai. Class IIa HDAC inhibition promotes an antitumor macrophage phenotype that induces breast tumor regression and inhibits metastasis [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B35.