High Antigenicity for T<sub>reg</sub> Cells Confers Resistance to <scp>PD</scp>‐1 Blockade Therapy via High <scp>PD</scp>‐1 Expression in T<sub>reg</sub> Cells
Regulatory T (T<sub>reg</sub>) cells have an immunosuppressive function, and programmed death-1 (PD-1)-expressing T<sub>reg</sub> cells reportedly induce resistance to PD-1 blockade therapies through their reactivation. However, the effects of antigenicity on PD-1 expression in T<sub>reg</sub> cells and the resistance to PD-1 blockade therapy remain unclear. Here, we show that T<sub>reg</sub> cells gain high PD-1 expression through an antigen with high antigenicity. Additionally, tumors with high antigenicity for T<sub>reg</sub> cells were resistant to PD-1 blockade in vivo due to PD-1<sup>+</sup> T<sub>reg</sub>-cell infiltration. Because such PD-1<sup>+</sup> T<sub>reg</sub> 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 T<sub>reg</sub> cell infiltration. We propose that the high antigenicity of T<sub>reg</sub> cells confers resistance to PD-1 blockade therapy via high PD-1 expression in T<sub>reg</sub> cells, which can be overcome by combination therapy with an anti-CTLA-4 mAb.
Authors
- Kadoaki Ohashi (ORCID: https://orcid.org/0000-0002-5180-3933)
- Takamasa Ishino (ORCID: https://orcid.org/0000-0002-8601-0677)
- Kiichiro Ninomiya (ORCID: https://orcid.org/0000-0002-2134-2865)
- Yoshinobu Maeda (ORCID: https://orcid.org/0000-0003-1634-5487)
- Yosuke Togashi (ORCID: https://orcid.org/0000-0001-9910-0164)
- Takashi Inozume (ORCID: https://orcid.org/0000-0001-7054-1863)
- Youki Ueda (ORCID: https://orcid.org/0000-0002-2627-8524)
- Hisae Matsuura (ORCID: https://orcid.org/0009-0009-5041-3042)
- Kota Tachibana (ORCID: https://orcid.org/0000-0003-3896-5732)
- Yoshinori Muto (ORCID: https://orcid.org/0000-0002-7757-0226)
- Joji Nagasaki (ORCID: https://orcid.org/0000-0003-0945-5469)
- Toshifumi Ninomiya (ORCID: https://orcid.org/0009-0006-0882-8154)
- Akiko Honobe‐Tabuchi (ORCID: https://orcid.org/0009-0006-8649-847X)
Institutions
- Chiba University (JP)
- Okayama University (JP)
- Okayama University Hospital (JP)
- University of Yamanashi (JP)
- Kindai University (JP)
Publication Details
- Journal
- Cancer Science
- Published
- 2025-02-27
- DOI
- https://doi.org/10.1111/cas.70029
- Citations
- 1
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- Canon Foundation in Europe
- Japan Agency for Medical Research and Development
- Canon Foundation for Scientific Research
- Japanese Respiratory Foundation
- Daiichi Sankyo Foundation of Life Science
- Ryobi Teien Memory Foundation
- MSD Life Science Foundation, Public Interest Incorporated Foundation
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Ube Foundation
- Daiichi Sankyo Europe