IL-6 receptor blockade impedes proinflammatory atypical Treg subset associated with immune checkpoint inhibitor–induced inflammatory arthritis
Year: 2026
Type: article
Abstract: BACKGROUNDImmune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) significantly impairs cancer therapy and patient quality of life, yet its pathogenic mechanisms remain unclear.METHODSThrough 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 coexpressing CD137 and IL-6R (AtpTreg).RESULTSThese cells exhibited reduced immunosuppressive capacity while aberrantly producing high levels 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.CONCLUSIONOur 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.TRIAL REGISTRATIONNCT07357636.FUNDINGThe National Natural Science Foundation of China General Fund Project; National Natural Science Foundation of China Youth Science Fund Project; Regional joint key support project of National Natural Science Foundation of China; Natural Science Foundation of Fujian Province; Joint Funds for the Innovation of Science and Technology, Fujian Province.
Authors: Yifei Ma, Nianqi Liu, Yan Li, Denghan Zhang, Shaohui He, Jun Lv, Yongluo Jiang, Guangmin Jian, Jingyao Zhang, Pengfei Zhu, Yue Ma, Jiacai Lin, Jin Li, Tong Wu, Yiwei Xu, Xiajie Lyu, Youlong Wang, Yiming Li, Yu Si Niu, Zhenyun Guo, Churong Lin, Ningnan Fang, Wei Jiang, Lihong Wang, Mengqin Yuan, Shenyue Wang, Shulin Huang, Qi Huang, Jinjian Li, Jun Lu, Bocen Chen, Guanqing Zhong, Haizhou Liu, Fadian Ding, Shangeng Weng, Rui Li, Ao Zhang
Institutions: Fujian Medical University, Shanxi Medical University, First Affiliated Hospital of Fujian Medical University, Taiyuan Central Hospital, Huazhong University of Science and Technology, Sun Yat-sen University, Capital Medical University, Beijing Tian Tan Hospital, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Second Military Medical University, Shanghai Changzheng Hospital, First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Danbury Hospital, Nuvance Health, Chinese PLA General Hospital, Chinese People's Liberation Army, Shantou University, First Affiliated Hospital of Shantou University Medical College, Shanxi Academy of Medical Sciences, Cancer Hospital of Shantou University Medical College, Jacobi Medical Center, Dallas County, Third Affiliated Hospital of Sun Yat-sen University, Hainan Medical University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
OpenAlex ID: W7160912628