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      Cancer immunotherapies targeting the PD-1 signaling pathway

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          Abstract

          Immunotherapy has recently emerged as the fourth pillar of cancer treatment, joining surgery, radiation, and chemotherapy. While early immunotherapies focused on accelerating T-cell activity, current immune-checkpoint inhibitors take the brakes off the anti-tumor immune responses. Successful clinical trials with PD-1 monoclonal antibodies and other immune-checkpoint inhibitors have opened new avenues in cancer immunology. However, the failure of a large subset of cancer patients to respond to these new immunotherapies has led to intensified research on combination therapies and predictive biomarkers. Here we summarize the development of PD-1-blockade immunotherapy and current issues in its clinical use.

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          Most cited references38

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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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            Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

            PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L) and is suggested to play a role in the maintenance of self-tolerance. In the present study, we examined possible roles of the PD-1/PD-L system in tumor immunity. Transgenic expression of PD-L1, one of the PD-L, in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro, and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L. Both effects could be reversed by anti-PD-L1 Ab. Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PD-L1. Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice. These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy.
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              Enhancement of antitumor immunity by CTLA-4 blockade.

              One reason for the poor immunogenicity of many tumors may be that they cannot provide signals for CD28-mediated costimulation necessary to fully activate T cells. It has recently become apparent that CTLA-4, a second counterreceptor for the B7 family of costimulatory molecules, is a negative regulator of T cell activation. Here, in vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors. Furthermore, this rejection resulted in immunity to a secondary exposure to tumor cells. These results suggest that blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune responses against tumor cells.
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                Author and article information

                Contributors
                yiwai@med.uoeh-u.ac.jp
                jnkhmns@kuhp.kyoto-u.ac.jp
                kchamoto@mfour.med.kyoto-u.ac.jp
                +81-75-753-4371 , honjo@mfour.med.kyoto-u.ac.jp
                Journal
                J Biomed Sci
                J. Biomed. Sci
                Journal of Biomedical Science
                BioMed Central (London )
                1021-7770
                1423-0127
                4 April 2017
                4 April 2017
                2017
                : 24
                : 26
                Affiliations
                [1 ]GRID grid.271052.3, Department of Molecular Biology, , School of Medicine, University of Occupational and Environmental Health Japan, ; Kitakyushu-shi, Fukuoka 807-8555 Japan
                [2 ]GRID grid.258799.8, Department of Immunology and Genomic Medicine, , Graduate School of Medicine, Kyoto University, ; Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501 Japan
                [3 ]GRID grid.258799.8, Department of Gynecology and Obstetrics, , Graduate School of Medicine, Kyoto University, ; 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507 Japan
                Article
                329
                10.1186/s12929-017-0329-9
                5381059
                28376884
                5fc3090e-da0a-4a71-be7e-4e51173c8eb1
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 10 March 2017
                : 20 March 2017
                Funding
                Funded by: The Uehara Memorial Foundation
                Funded by: The Soroptimist Japan Foundation
                Funded by: Grant-in-Aid for Scientific Research (B)
                Award ID: 26293359
                Award Recipient :
                Funded by: Daiichi Sankyo grant program (TaNeDS)
                Funded by: (AMED) Grants
                Award ID: 145208
                Award Recipient :
                Funded by: (AMED) Grants
                Award ID: 16770835
                Award Recipient :
                Funded by: Tang Prize Foundation
                Funded by: the Cell Science Foundation
                Funded by: Grant-in-Aid for Young Scientists (A) Grant
                Award ID: 16748159
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2017

                Molecular medicine
                pd-1,pd-l1,cancer immunotherapy,immune checkpoint
                Molecular medicine
                pd-1, pd-l1, cancer immunotherapy, immune checkpoint

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