IL-6 receptor blockade impedes proinflammatory atypical Treg subset associated with immune checkpoint inhibitor–induced inflammatory arthritis
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
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
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Clinical Research and Public Health Immunology Oncology

IL-6 receptor blockade impedes proinflammatory atypical Treg subset associated with immune checkpoint inhibitor–induced inflammatory arthritis

Abstract

BACKGROUND Immune checkpoint inhibitor–induced inflammatory arthritis (ICI-IA) significantly impairs cancer therapy and patient quality of life, yet its pathogenic mechanisms remain unclear.METHODS 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 coexpressing CD137 and IL-6R (AtpTreg).RESULTS These 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.CONCLUSION 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.TRIAL REGISTRATION NCT07357636.FUNDING The 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

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Figure 4

AtpTreg is associated with poor arthritis prognosis but better survival outcomes of cancer patients.

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AtpTreg is associated with poor arthritis prognosis but better survival ...
(A) Research flowchart showing single-cell surface proteomics coupled with Sc-VDJseq of bead-enriched Treg cells from paired samples of blood, synovial fluid (SF), as well as tumor of ICI-IA, serial clinical assessment follow-up protocols, and function experiments, related to Supplemental Table 2. (B–F) Correlation plot showing the proportion of overall AtpTreg cells in each patient and MRI imaging (WIPE scores, B), clinical disease activity (CDAI scores, C), adverse event severity (CTCAE scores, D), serum CRP values (E), and cancer patients’ quality of life (FACT-G scores, F). *P < 0.05, **P < 0.01, ***P < 0.001. (G and H) Dynamics of MRI imaging (WIPE scores, mean ± SEM, G) and serum CRP values (mean ± SEM, H), of 4 timepoints during 12-month follow up since onset in patients with ICI-IA, categorized by high and low median value of overall AtpTreg cell proportions in each patient. *P < 0.05, **P < 0.01, ***P < 0.001, calculated with independent Wilcoxon signed-rank test. (I and J) Dynamics of clinical disease activity (CDAI scores, mean ± SEM, I) and quality of life (FACT-G scores, mean ± SEM, J), of 4 timepoints during 12-month follow-up since onset in patients with ICI-IA, categorized by high and low median value of overall AtpTreg cell proportions in each patient. *P < 0.05, **P < 0.01, ***P < 0.001, calculated with independent Wilcoxon signed-rank test. (K) Kaplan-Meier survival curve showing survival time (since ICI treatment) of patients with gastric cancer, categorized by high and low median value of overall AtpTreg cell proportions in each patient, with difference of survival rate calculated with log-rank test (P = 0.02).