Single cell profiling identifies effector CD8+ T cells and peripheral helper T cells as drivers of recurrent immunotherapy mediated arthritis 2328826

Abstract Introduction Immune checkpoint inhibitor (ICI) therapy is often associated with inflammatory arthritis (ICI-IA). However, the mechanisms underlying ICI-IA, especially its recurrence, have not been fully elucidated. The purpose of this study is to elucidate mechanisms of recurrent ICI-IA by analyzing longitudinal synovial fluid (SF) samples. Methods SF samples were collected from ICI-IA patients at the first and second occurrences of ICI-IA and analyzed with single-cell RNA sequencing (scRNAseq), scTCRseq, scBCRseq, and flow cytometry. SF samples from cancer-naïve osteoarthritis patients were used as negative controls. Results Effector CD8+ T cells and PD-1hi CXCL13hi CD4+ T cells were enriched in the SF of ICI-IA patients. Ninety three percent and fifty percent of the top ten expanded clones of effector CD8+ T cells and PD-1hi CXCL13hi CD4+ T cells, respectively, were shared between the first and second ICI-IA flare. They were more clonally expanded and characterized by the production of pro-inflammatory cytokines including IFNγ, TNFα, and IL-21, especially in the second flare, suggesting immune memory responses to cognate antigen. Cell-cell communication analysis suggests that effector CD8+ T cells and PD-1hi CXCL13hi CD4+ T cells interact with each other and with myeloid cells and B cells through chemokines (CXCL9/10/11/13, CCL5) and cytokines (MIF, IL-2/7/15/21). Conclusion Longitudinal SF analysis from ICI-IA patients for first time revealed that expansion of effector CD8+ T cells and PD-1hi CXCL13hi CD4+ T cells with proinflammatory characteristics Funding Source n/a Topic Categories Basic Autoimmunity (BA)