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      TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

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          ABSTRACT

          The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc + tumors, we found that TIGIT expression was upregulated on CD8 + and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.

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          Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

          The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
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            The blockade of immune checkpoints in cancer immunotherapy.

            Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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              Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

              Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.
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                Author and article information

                Journal
                Oncoimmunology
                Oncoimmunology
                KONI
                koni20
                Oncoimmunology
                Taylor & Francis
                2162-4011
                2162-402X
                2018
                24 May 2018
                24 May 2018
                : 7
                : 8
                : e1466769
                Affiliations
                [a ]Department of Neurosurgery, Johns Hopkins Hospital , Baltimore, MD, USA
                [b ]Department of Oncology, Johns Hopkins Hospital , Baltimore, MD, USA
                [c ]Bristol-Myers Squibb , New York, NY, USA
                [d ]Wide River Institute of Immunology, Seoul National University College of Medicine , Hongcheon, Korea
                [e ]Department of Biomedical Sciences, Seoul National University College of Medicine , Seoul, Korea
                [f ]Department of Neurosurgery, Seoul National University College of Medicine , Seoul, Korea
                Author notes
                CONTACT Michael Lim, M.D. mlim3@ 123456jhmi.edu Johns Hopkins Hospital, 600 N. Wolfe Street, Department of Neurosurgery – Phipps 123 , Baltimore, MD 21287

                Supplemental data for this article can be accessed at: https://doi.org/10.1080/2162402X.2018.1466769.

                [#]

                These authors have contributed equally.

                Author information
                http://orcid.org/0000-0002-0792-6880
                http://orcid.org/0000-0002-5469-4058
                http://orcid.org/0000-0001-6152-8392
                http://orcid.org/0000-0002-3158-0947
                http://orcid.org/0000-0002-1142-8542
                Article
                1466769
                10.1080/2162402X.2018.1466769
                6136875
                30221069
                237d752d-8a2f-43bd-9054-d404ccc331eb
                © 2018 The Author(s). Published with Taylor & Francis Group.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

                History
                : 26 February 2018
                : 11 April 2018
                : 13 April 2018
                Page count
                Figures: 8, Tables: 0, Equations: 0, References: 67, Pages: 13
                Funding
                Funded by: Bloomberg-Kimmel Institute for Cancer Immunotherapy and CCSG Grant (Dr. Nelson, PI)
                Award ID: P30CA006973
                Bloomberg-Kimmel Institute for Cancer Immunotherapy and CCSG Grant (Dr. Nelson, PI) P30CA006973
                Categories
                Original Research

                Immunology
                tigit,pvr,cd155,pd-1,dendritic cell,glioma,checkpoint inhibitor,immunotherapy,gbm
                Immunology
                tigit, pvr, cd155, pd-1, dendritic cell, glioma, checkpoint inhibitor, immunotherapy, gbm

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