Immune hallmarks of recurrent immune checkpoint inhibitor-mediated inflammatory arthritis

Immune checkpoint inhibitor (ICI) therapy is often associated with immune-related adverse events including inflammatory arthritis (ICI-IA). However, the mechanisms underlying ICI-IA, especially its recurrence, have not been fully investigated. The purpose of this study is to elucidate mechanisms of recurrent ICI-IA by analyzing longitudinal synovial fluid (SF) samples. SF samples were collected from six ICI-IA patients at the first and second occurrences of ICI-IA and analyzed with single-cell RNA sequencing (scRNAseq) (n=3), scTCRseq (n=3), scBCRseq (n=3), and flow cytometry (n=6). SF samples from cancer-naïve osteoarthritis patients (n=6) were used as negative controls. Analysis revealed that 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. These top clones were characterized by the production of pro-inflammatory type 1 cytokines including IFNg, TNFa, 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 interacted with each other and with myeloid cells and B cells through chemokines (CXCL9/10/11/13, CCL3) and cytokines (MIF, IL-2/7/15/21). Overall, longitudinal SF analysis from ICI-IA patients for the first time revealed the expansion of effector CD8+ T cells and PD-1hi CXCL13hi CD4+ T cells with type 1 cytokine signatures that potentially contribute to development or recurrence of ICI-IA.