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High Antigenicity for Treg Cells Confers Resistance to PD-1 Blockade Therapy via High PD-1 Expression in Treg Cells

Year: 2025
Type: article
Abstract: Regulatory T (Treg) cells have an immunosuppressive function, and programmed death-1 (PD-1)-expressing Treg cells reportedly induce resistance to PD-1 blockade therapies through their reactivation. However, the effects of antigenicity on PD-1 expression in Treg cells and the resistance to PD-1 blockade therapy remain unclear. Here, we show that Treg cells gain high PD-1 expression through an antigen with high antigenicity. Additionally, tumors with high antigenicity for Treg cells were resistant to PD-1 blockade in vivo due to PD-1+ Treg-cell infiltration. Because such PD-1+ Treg cells have high cytotoxic T lymphocyte antigen (CTLA)-4 expression, resistance could be overcome by combination with an anti-CTLA-4 monoclonal antibody (mAb). Patients who responded to combination therapy with anti-PD-1 and anti-CTLA-4 mAbs sequentially after primary resistance to PD-1 blockade monotherapy showed high Treg cell infiltration. We propose that the high antigenicity of Treg cells confers resistance to PD-1 blockade therapy via high PD-1 expression in Treg cells, which can be overcome by combination therapy with an anti-CTLA-4 mAb.
Authors: Matsuura, Hiroaki, Ishino, Takamasa, Ninomiya, Toshifumi, Ninomiya, Kiichiro, Tachibana, Kota, Honobe-Tabuchi, Akiko, Muto, Yoshinori, Inozume, Takashi, Ueda, Youki, Ohashi, Kadoaki, Maeda, Yoshinobu, Nagasaki, Joji, Togashi, Yosuke
Language: English
Subfield: Oncology
Field: Medicine
Open Access status: green
Funders: Canon Foundation in Europe, Japan Agency for Medical Research and Development, Japanese Respiratory Foundation, Daiichi Sankyo Foundation of Life Science, Ryobi Teien Memory Foundation, Japan Society for the Promotion of Science, Japan Science and Technology Agency, Ube Foundation, Daiichi Sankyo Europe
OpenAlex ID: W7113100462
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