IL-6 receptor blockade impedes proinflammatory atypical Treg subset associated with immune checkpoint inhibitor-induced inflammatory arthritis
Immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) significantly impairs cancer therapy and patient quality of life, yet its pathogenic mechanisms remain unclear. Through integrated single-cell multi-omics analysis of paired peripheral blood, synovial fluid, and tumor samples from longitudinal ICI-IA cohorts and matched controls, we identified a unique regulatory T-cell (Treg) population co-expressing CD137 and IL-6R (AtpTreg). These cells exhibited reduced immunosuppressive capacity while aberrantly producing high level of IL-17 and promoting proinflammatory responses of synoviocytes. AtpTreg exhibits shared clonotypes and phenotypes across tissue compartments. Notably, AtpTreg frequency correlates with increased arthritis severity yet paradoxically associates with improved overall survival. Anti-IL6R therapy reduced AtpTreg levels, corresponding with improved arthritis outcomes and quality of life, without compromising anti-tumor immunity. Our findings define a pathogenic Treg subset in ICI-IA and validate IL-6R blockade as a mechanism-based therapeutic strategy, bridging mechanistic discovery to clinical translation. This study is registered at ClinicalTrials.gov (NCT07357636).
Authors
- Nianqi Liu (ORCID: https://orcid.org/0000-0002-5520-1075)
- Yu Si Niu
- Xiajie Lyu
- Fadian Ding (ORCID: https://orcid.org/0000-0002-9868-3094)
- Zhenyun Guo
- Shaohui He (ORCID: https://orcid.org/0000-0003-3569-0059)
- Jiacai Lin (ORCID: https://orcid.org/0000-0002-2921-7954)
- Bocen Chen
- Yongluo Jiang (ORCID: https://orcid.org/0000-0002-3456-0570)
- Guangmin Jian
- Haizhou Liu (ORCID: https://orcid.org/0000-0001-5111-5295)
- Jinjian Li (ORCID: https://orcid.org/0009-0008-3366-3448)
- Youlong Wang (ORCID: https://orcid.org/0000-0002-0289-7005)
- Denghan Zhang
- Ningnan Fang
- Yan Li (ORCID: https://orcid.org/0000-0002-6336-0981)
- Jun Lv
- Churong Lin
- Yifei Ma
- Qi Huang
- Shulin Huang
- Jin Li (ORCID: https://orcid.org/0009-0005-4024-264X)
- Jingyao Zhang
- Shenyue Wang
- Pengfei Zhu
- Tong Wu
- Yue Ma
- Shangeng Weng
- Yiming Li
- Wei Jiang
- Mengqin Yuan
- Rui Li (ORCID: https://orcid.org/0000-0002-7210-8358)
- Guanqing Zhong
- Yiwei Xu
- Ao Zhang (ORCID: https://orcid.org/0009-0004-0485-7244)
- Jun Lu
- Lihong Wang
Institutions
- Fujian Medical University (CN)
- Sun Yat-sen University (CN)
- Shanxi Medical University (CN)
- Capital Medical University (CN)
- Dallas County (US)
- Danbury Hospital (US)
- Jacobi Medical Center (US)
- Chinese PLA General Hospital (CN)
- Shantou University (CN)
- Beijing Tian Tan Hospital (CN)
- Cancer Hospital of Shantou University Medical College (CN)
- Shanghai Changzheng Hospital (CN)
- First Affiliated Hospital of Shantou University Medical College (CN)
- First Affiliated Hospital of Fujian Medical University (CN)
- Hainan General Hospital (CN)
- Hainan 301 Hospital (CN)
- Taiyuan Central Hospital (CN)
- Sun Yat-sen University Cancer Center (CN)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- Shanxi Academy of Medical Sciences (CN)
- Huazhong University of Science and Technology (CN)
- Hainan Medical University (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-05-12
- DOI
- https://doi.org/10.1172/jci200135
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00