High Antigenicity for Treg Cells Confers Resistance to PD‐1 Blockade Therapy via High PD‐1 Expression in Treg Cells
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 P...
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| Published in | Cancer science Vol. 116; no. 5; pp. 1214 - 1226 |
|---|---|
| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Tokyo
John Wiley & Sons, Inc
01.05.2025
John Wiley and Sons Inc |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1347-9032 1349-7006 1349-7006 |
| DOI | 10.1111/cas.70029 |
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| Abstract | 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.
High antigenicity of Treg cells confers resistance to anti‐PD‐1 mAb monotherapy via high PD‐1 expression in Treg cells. Resistance to anti‐PD‐1 mAb monotherapy via high PD‐1 expression in Treg cells can be overcome by combination therapy with an anti‐CTLA‐4 mAb. PD‐1+ Treg cells in the TME and Treg cell antigens may be predictive biomarkers for combination therapy with anti‐PD‐1 and anti‐CTLA‐4 mAbs. |
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| AbstractList | 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.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. Regulatory T (T[sub.reg]) cells have an immunosuppressive function, and programmed death‐1 (PD‐1)‐expressing T[sub.reg] 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] cells and the resistance to PD‐1 blockade therapy remain unclear. Here, we show that T[sub.reg] cells gain high PD‐1 expression through an antigen with high antigenicity. Additionally, tumors with high antigenicity for T[sub.reg] cells were resistant to PD‐1 blockade in vivo due to PD‐1[sup.+] T[sub.reg]‐cell infiltration. Because such PD‐1[sup.+] T[sub.reg] 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] cell infiltration. We propose that the high antigenicity of T[sub.reg] cells confers resistance to PD‐1 blockade therapy via high PD‐1 expression in T[sub.reg] cells, which can be overcome by combination therapy with an anti‐CTLA‐4 mAb. Regulatory T (T reg ) cells have an immunosuppressive function, and programmed death‐1 (PD‐1)‐expressing T reg cells reportedly induce resistance to PD‐1 blockade therapies through their reactivation. However, the effects of antigenicity on PD‐1 expression in T reg cells and the resistance to PD‐1 blockade therapy remain unclear. Here, we show that T reg cells gain high PD‐1 expression through an antigen with high antigenicity. Additionally, tumors with high antigenicity for T reg cells were resistant to PD‐1 blockade in vivo due to PD‐1 + T reg ‐cell infiltration. Because such PD‐1 + T reg 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 reg cell infiltration. We propose that the high antigenicity of T reg cells confers resistance to PD‐1 blockade therapy via high PD‐1 expression in T reg cells, which can be overcome by combination therapy with an anti‐CTLA‐4 mAb. High antigenicity of T reg cells confers resistance to anti‐PD‐1 mAb monotherapy via high PD‐1 expression in T reg cells. Resistance to anti‐PD‐1 mAb monotherapy via high PD‐1 expression in T reg cells can be overcome by combination therapy with an anti‐CTLA‐4 mAb. PD‐1 + T reg cells in the TME and T reg cell antigens may be predictive biomarkers for combination therapy with anti‐PD‐1 and anti‐CTLA‐4 mAbs. 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. High antigenicity of Treg cells confers resistance to anti‐PD‐1 mAb monotherapy via high PD‐1 expression in Treg cells. Resistance to anti‐PD‐1 mAb monotherapy via high PD‐1 expression in Treg cells can be overcome by combination therapy with an anti‐CTLA‐4 mAb. PD‐1+ Treg cells in the TME and Treg cell antigens may be predictive biomarkers for combination therapy with anti‐PD‐1 and anti‐CTLA‐4 mAbs. 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. |
| Audience | Academic |
| Author | Ueda, Youki Togashi, Yosuke Ishino, Takamasa Inozume, Takashi Matsuura, Hiroaki Muto, Yoshinori Ninomiya, Kiichiro Maeda, Yoshinobu Nagasaki, Joji Ninomiya, Toshifumi Tachibana, Kota Honobe‐Tabuchi, Akiko Ohashi, Kadoaki |
| AuthorAffiliation | 2 Department of Hematology, Oncology and Respiratory Medicine Okayama University Okayama Japan 7 Kindai University Faculty of Medicine Osaka Japan 1 Department of Tumor Microenvironment Okayama University Okayama Japan 3 Department of Dermatology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan 6 Department of Allergy and Respiratory Medicine Okayama University Hospital Okayama Japan 4 Department of Dermatology University of Yamanashi Yamanashi Japan 5 Department of Dermatology Chiba University Chiba Japan |
| AuthorAffiliation_xml | – name: 3 Department of Dermatology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan – name: 1 Department of Tumor Microenvironment Okayama University Okayama Japan – name: 6 Department of Allergy and Respiratory Medicine Okayama University Hospital Okayama Japan – name: 4 Department of Dermatology University of Yamanashi Yamanashi Japan – name: 7 Kindai University Faculty of Medicine Osaka Japan – name: 2 Department of Hematology, Oncology and Respiratory Medicine Okayama University Okayama Japan – name: 5 Department of Dermatology Chiba University Chiba Japan |
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| Copyright | 2025 The Author(s). published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. COPYRIGHT 2025 John Wiley & Sons, Inc. 2025. This work is published under http://creativecommons.org/licenses/by-nc/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2025 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. |
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| Notes | Funding This research was supported by grants from the Japan Society for the Promotion of Science (JSPS) (JP20H03694 [Y. Togashi], JP21K20859 [T. Ishino], and JP22K15607 [K. Ninomiya]); Japan Agency for Medical Research and Development (AMED) (JP23ama221324h0001 [J. Nagasaki]); Japan Science and Technology Agency (JST) JPMJFR2049 (Y. Togashi); Canon Foundation (Y. Togashi); Daiichi Sankyo Foundation of Life Science (Y. Togashi); MSD Life Science Foundation (Y. Togashi); Japanese Respiratory Foundation (Y. Togashi); UBE Foundation (Y. Togashi); Ryobi Teien Memory Foundation (J. Nagasaki). ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Funding: This research was supported by grants from the Japan Society for the Promotion of Science (JSPS) (JP20H03694 [Y. Togashi], JP21K20859 [T. Ishino], and JP22K15607 [K. Ninomiya]); Japan Agency for Medical Research and Development (AMED) (JP23ama221324h0001 [J. Nagasaki]); Japan Science and Technology Agency (JST) JPMJFR2049 (Y. Togashi); Canon Foundation (Y. Togashi); Daiichi Sankyo Foundation of Life Science (Y. Togashi); MSD Life Science Foundation (Y. Togashi); Japanese Respiratory Foundation (Y. Togashi); UBE Foundation (Y. Togashi); Ryobi Teien Memory Foundation (J. Nagasaki). |
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| References | 2017; 20 2019; 4 2013; 1 2012; 366 2023; 34 1990; 18 2023; 8 1988; 54 2019; 16 2002; 3 1999; 163 2024; 12 1995; 155 2019; 381 2020; 19 2012; 209 2022; 386 2009; 30 2023; 24 2022; 40 2017; 38 2007; 110 2021; 39 2015; 112 1999; 59 2018; 378 2015; 373 2001; 8 2019; 116 2014; 15 2013; 210 2020; 48 2023; 114 2000; 164 2001; 2 2021; 397 2022; 605 2020; 21 1996; 8 2018; 36 2011; 187 2006; 103 |
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| Snippet | ABSTRACT
Regulatory T (Treg) cells have an immunosuppressive function, and programmed death‐1 (PD‐1)‐expressing Treg cells reportedly induce resistance to PD‐1... Regulatory T (T[sub.reg]) cells have an immunosuppressive function, and programmed death‐1 (PD‐1)‐expressing T[sub.reg] cells reportedly induce resistance to... ABSTRACT Regulatory T (Treg) cells have an immunosuppressive function, and programmed death‐1 (PD‐1)‐expressing Treg cells reportedly induce resistance to PD‐1... Regulatory T (Treg) cells have an immunosuppressive function, and programmed death-1 (PD-1)-expressing Treg cells reportedly induce resistance to PD-1 blockade... Regulatory T (T reg ) cells have an immunosuppressive function, and programmed death‐1 (PD‐1)‐expressing T reg cells reportedly induce resistance to PD‐1... |
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| SubjectTerms | Antibodies Antigenicity Antigens Apoptosis Cancer cancer immunotherapy Cell death Cloning Combination therapy CTLA‐4 Cytotoxicity Experiments Females Flow cytometry Infiltration Ipilimumab Laboratory animals Ligands Lymphocytes Lymphocytes T Melanoma Metastases Monoclonal antibodies Mutagenesis Original ORIGINAL ARTICLE PD‐1 Peptides regulatory T cell T cell receptors T cells Tumors |
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| Title | High Antigenicity for Treg Cells Confers Resistance to PD‐1 Blockade Therapy via High PD‐1 Expression in Treg Cells |
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