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      Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy

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          Abstract

          CD8 + T cell-mediated cancer clearance is often suppressed by the interaction between inhibitory molecules like PD-1 and PD-L1, an interaction acts like brakes to prevent T cell overreaction under normal conditions but is exploited by tumor cells to escape the immune surveillance. Immune checkpoint inhibitors have revolutionized cancer therapeutics by removing such brakes. Unfortunately, only a minority of cancer patients respond to immunotherapies presumably due to inadequate immunity. Antitumor immunity depends on the activation of the cGAS-STING pathway, as STING-deficient mice fail to stimulate tumor-infiltrating dendritic cells (DCs) to activate CD8 + T cells. STING agonists also enhance natural killer (NK) cells to mediate the clearance of CD8 + T cell-resistant tumors. Therefore STING agonists have been intensively sought after. We previously discovered that manganese (Mn) is indispensable for the host defense against cytosolic dsDNA by activating cGAS-STING. Here we report that Mn is also essential in innate immune sensing of tumors and enhances adaptive immune responses against tumors. Mn-insufficient mice had significantly enhanced tumor growth and metastasis, with greatly reduced tumor-infiltrating CD8 + T cells. Mechanically, Mn 2+ promoted DC and macrophage maturation and tumor-specific antigen presentation, augmented CD8 + T cell differentiation, activation and NK cell activation, and increased memory CD8 + T cells. Combining Mn 2+ with immune checkpoint inhibition synergistically boosted antitumor efficacies and reduced the anti-PD-1 antibody dosage required in mice. Importantly, a completed phase 1 clinical trial with the combined regimen of Mn 2+ and anti-PD-1 antibody showed promising efficacy, exhibiting type I IFN induction, manageable safety and revived responses to immunotherapy in most patients with advanced metastatic solid tumors. We propose that this combination strategy warrants further clinical translation.

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          Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer

          First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.
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            Immune checkpoint blockade: a common denominator approach to cancer therapy.

            The immune system recognizes and is poised to eliminate cancer but is held in check by inhibitory receptors and ligands. These immune checkpoint pathways, which normally maintain self-tolerance and limit collateral tissue damage during anti-microbial immune responses, can be co-opted by cancer to evade immune destruction. Drugs interrupting immune checkpoints, such as anti-CTLA-4, anti-PD-1, anti-PD-L1, and others in early development, can unleash anti-tumor immunity and mediate durable cancer regressions. The complex biology of immune checkpoint pathways still contains many mysteries, and the full activity spectrum of checkpoint-blocking drugs, used alone or in combination, is currently the subject of intense study. Copyright © 2015 Elsevier Inc. All rights reserved.
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              Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation

              PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor–mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon γ, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.
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                Author and article information

                Contributors
                meiqnn@hotmail.com
                hanwdrsw69@yahoo.com
                jiangzf@pku.edu.cn
                Journal
                Cell Res
                Cell Res
                Cell Research
                Springer Singapore (Singapore )
                1001-0602
                1748-7838
                24 August 2020
                24 August 2020
                November 2020
                : 30
                : 11
                : 966-979
                Affiliations
                [1 ]GRID grid.11135.37, ISNI 0000 0001 2256 9319, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, , Peking University, ; Beijing, 100871 China
                [2 ]GRID grid.11135.37, ISNI 0000 0001 2256 9319, Peking-Tsinghua Center for Life Sciences, , Peking University, ; Beijing, 100871 China
                [3 ]GRID grid.414252.4, ISNI 0000 0004 1761 8894, Department of Bio-therapeutic, the First Medical Center, , Chinese PLA General Hospital, ; Beijing, 100853 China
                [4 ]GRID grid.12527.33, ISNI 0000 0001 0662 3178, Institute for Immunology, Peking-Tsinghua Center for Life Sciences, School of Medicine, , Tsinghua University, ; Beijing, 100084 China
                [5 ]GRID grid.5386.8, ISNI 000000041936877X, Present Address: Jill Roberts Institute for Research in Inflammatory Bowel Disease (JRI), , Weill Cornell Medicine, Cornell University, ; New York, NY USA
                [6 ]GRID grid.48336.3a, ISNI 0000 0004 1936 8075, Present Address: Experimental Immunology Branch, , National Cancer Institute, National Institutes of Health, ; Bethesda, MD USA
                Author information
                http://orcid.org/0000-0002-8509-7969
                http://orcid.org/0000-0001-9312-0164
                http://orcid.org/0000-0003-3207-3899
                http://orcid.org/0000-0002-1247-1382
                Article
                395
                10.1038/s41422-020-00395-4
                7785004
                32839553
                42678bc1-4b5b-4481-8e63-7febe27db2be
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 27 April 2020
                : 3 August 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 31830022
                Award ID: 81621001
                Award ID: 81830002
                Award ID: 81773248
                Award ID: 81773248
                Award ID: 81830002
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100002855, Ministry of Science and Technology of the People’s Republic of China (Chinese Ministry of Science and Technology);
                Award ID: 2019YFA0508500
                Award Recipient :
                Categories
                Article
                Custom metadata
                © Center for Excellence in Molecular Cell Science, CAS 2020

                Cell biology
                pattern recognition receptors,immunosurveillance
                Cell biology
                pattern recognition receptors, immunosurveillance

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