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Activated CTLA-4-independent immunosuppression of Treg cells disturbs CTLA-4 blockade-mediated antitumor immunity.
Watanabe, Tomofumi; Ishino, Takamasa; Ueda, Youki; Nagasaki, Joji; Sadahira, Takuya; Dansako, Hiromichi; Araki, Motoo; Togashi, Yosuke.
Afiliación
  • Watanabe T; Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
  • Ishino T; Department of Urology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
  • Ueda Y; Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
  • Nagasaki J; Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • Sadahira T; Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
  • Dansako H; Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
  • Araki M; Department of Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
  • Togashi Y; Department of Urology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Cancer Sci ; 114(5): 1859-1870, 2023 May.
Article en En | MEDLINE | ID: mdl-36762794
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / Neoplasias Renales Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cancer Sci Año: 2023 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / Neoplasias Renales Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cancer Sci Año: 2023 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Reino Unido