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      Activated CTLA‐4‐independent immunosuppression of Treg cells disturbs CTLA‐4 blockade‐mediated antitumor immunity


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          Combination therapy with anti‐cytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) and anti‐programmed death‐1 (PD‐1) monoclonal antibodies (mAbs) has dramatically improved the prognosis of patients with multiple types of cancer, including renal cell carcinoma (RCC). However, more than half of RCC patients fail to respond to this therapy. Regulatory T cells (Treg cells) are a subset of highly immunosuppressive CD4 + T cells that promote the immune escape of tumors by suppressing effector T cells in the tumor microenvironment (TME) through various mechanisms. CTLA‐4 is constitutively expressed in Treg cells and is regarded as a key molecule for Treg‐cell‐mediated immunosuppressive functions, suppressing antigen‐presenting cells by binding to CD80/CD86. Reducing Treg cells in the TME with an anti‐CTLA‐4 mAb with antibody‐dependent cellular cytotoxicity (ADCC) activity is considered an essential mechanism to achieve tumor regression. In contrast, we demonstrated that CTLA‐4 blockade without ADCC activity enhanced CD28 costimulatory signaling pathways in Treg cells and promoted Treg‐cell proliferation in mouse models. CTLA‐4 blockade also augmented CTLA‐4‐independent immunosuppressive functions, including cytokine production, leading to insufficient antitumor effects. Similar results were also observed in human peripheral blood lymphocytes and tumor‐infiltrating lymphocytes from patients with RCC. Our findings highlight the importance of Treg‐cell depletion to achieve tumor regression in response to CTLA‐4 blockade therapies.


          CTLA‐4 blockade without ADCC activity augments the proliferation and CTLA‐4‐independent immunosuppressive functions of Treg cells by enhancing CD28 costimulatory signaling pathways in Treg cells, leading to insufficient tumor regression. This figure was created with BioRender.com.

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          Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

          This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
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            Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma

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              Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma.

                Author and article information

                Cancer Sci
                Cancer Sci
                Cancer Science
                John Wiley and Sons Inc. (Hoboken )
                26 February 2023
                May 2023
                : 114
                : 5 ( doiID: 10.1111/cas.v114.5 )
                : 1859-1870
                [ 1 ] Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan
                [ 2 ] Department of Urology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan
                [ 3 ] Department of Gastroenterology, Graduate School of Medicine Chiba University Chiba Japan
                [ 4 ] Department of Hematology, Graduate School of Medicine Osaka Metropolitan University Osaka Japan
                Author notes
                [*] [* ] Correspondence

                Yosuke Togashi, Department of Tumor microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. 2‐5‐1 Shikata‐cho, Kita‐ku, Okayama, 700‐8558, Japan.

                Email: ytogashi1584@ 123456gmail.com

                Author information
                CAS15756 CAS-OA-2627-2022.R1
                © 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                : 31 January 2023
                : 30 November 2022
                : 06 February 2023
                Page count
                Figures: 7, Tables: 0, Pages: 12, Words: 6705
                Funded by: Inamori Foundation , doi 10.13039/501100003844;
                Funded by: Japan Agency for Medical Research and Development , doi 10.13039/100009619;
                Award ID: 21cm0106383
                Award ID: 22ck0106723h0001
                Funded by: Japan Respiratory Foundation
                Funded by: Japan Science and Technology Agency , doi 10.13039/501100002241;
                Award ID: 21‐211033868
                Funded by: Japan Society for the Promotion of Science , doi 10.13039/501100001691;
                Award ID: 20H03694
                Award ID: 22K1945904
                Funded by: Kato Memorial Bioscience Foundation , doi 10.13039/501100004051;
                Funded by: MSD Life Science Foundation, Public Interest Incorporated Foundation , doi 10.13039/501100013236;
                Funded by: Naito Foundation , doi 10.13039/100007428;
                Funded by: Ono Medical Research Foundation , doi 10.13039/501100008664;
                Funded by: Pharmacology Research Foundation
                Funded by: Princess Takamatsu Cancer Research Fund , doi 10.13039/501100008886;
                Funded by: Senri Life Science Foundation , doi 10.13039/501100008801;
                Funded by: Takeda Science Foundation , doi 10.13039/100007449;
                Funded by: Ube Industries , doi 10.13039/501100008888;
                Funded by: Wesco Science Foundation , doi 10.13039/100016189;
                Original Article
                ORIGINAL ARTICLES
                Basic and Clinical Immunology
                Custom metadata
                May 2023
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.8 mode:remove_FC converted:03.05.2023

                Oncology & Radiotherapy
                antibody‐dependent cell cytotoxicity,cytotoxic t‐lymphocyte‐associated antigen 4,immune checkpoint inhibitors,regulatory t cell,renal cell carcinoma


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