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 2

An atypical Treg cell type as signature of inflammatory arthritis after checkpoint blockade.

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An atypical Treg cell type as signature of inflammatory arthritis after ...
(A) Research flowchart of single-cell surface proteomics of peripheral blood mononuclear cells from ICI-IA (17,323 cells, n = 5), RA-CA (17,541 cells, n = 4) and ICI-NC (18,619 cells, n = 5). (B) Annotated UMAP clustering defined by single-cell surface proteomics of blood samples of ICI-IA, RA-CA, and ICI-NC. (C) Distribution of cell clusters in each group. (D) Distribution of Treg cells per patient in each group. (E) UMAP subclustering of Treg cells (3,744 cells) from the original single-cell surface proteomics samples. (F) Signature proteins of the 2 Treg subclusters depicted as the bubble plot. (G) Distribution of Treg subclusters in each group, showing ICI-IA group has high percentage cluster # 0. (H) Research flowchart of single-cell RNA-seq (11,864 cells) of bead-enriched Treg cells. (I) UMAP clustering defined by single-cell RNA-seq of blood Treg cells of all samples. (J) Signature proteins. (K) Distribution of single-cell RNA-seq–defined cell clusters in each group. (L) GSEA of differential genes in cluster # 2. (M) Th17 scoring in each cluster. (N) Heatmap of average expression of each marker of single-cell secreting proteomics of AtpTreg and other Tregs per sample. (O and P) Treg suppression assay with Tregs for Tresp from healthy controls. FlowJo figures are shown for CFSE negative cells at a Tresp‑to‑Treg ratio of 1:4. (O) and suppression analysis plot shown (P). (Q) OLINK proteomics of human synovial lines (MH7A) cocultured with blood-derived Treg cells of patients with ICI-IA, as compared with human synovial lines (MH7A) without coculture system. (R and S) ELISA test of stromelysin MMP-10 (R) and stromelysin MMP-3 (S) in MH7A in coculture system. (T) CCK-8 test of cell counts of MH7A in coculture system. **P < 0.01, ***P < 0.001, calculated using an independent Wilcoxon test. *P < 0.05, **P < 0.01, ***P < 0.001, calculated with independent Wilcoxon signed-rank test.