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

• DOI: 10.1111/cas.15756
• Publication Date: 2023-02-10T12:59:47Z
• Authors: Tomofumi Watanabe; Takamasa Ishino; Youki Ueda; Joji Nagasaki; Takuya Sadahira; Hiromichi Dansako; Motoo Araki; Yosuke Togashi
• Keywords: CTLA-4; Immunosuppression

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