Background/Purpose: Immune checkpoint inhibitor (ICI) therapy is associated with life- and/or organ-threatening immune-related adverse events, including inflammatory arthritis (ICI-IA). However, the mechanisms behind ICI-IA, especially when it recurs, have not been fully elucidated. Thus, longitudinal sample analyses provide valuable information to understand disease pathogenesis. The purpose of the study is to elucidate mechanisms of ICI-IA by analyzing longitudinal synovial fluid (SF) samples.

Methods: SF samples were collected from six ICI-IA patients at the first and second occurrences of the IA flare and analyzed with single-cell RNA sequencing (scRNAseq), scTCRseq, scBCRseq, and flow cytometry. SF samples from cancer-naïve osteoarthritis (OA) patients were used as negative controls.

Results: SF effector CD8+ T cells and PD-1hi CXCL13hi CD4+ T cells were clonally expanded, implying their role in ICI-IA pathogenesis. Ninety three % of the top 10 expanded effector CD8+ T cell clones were shared between the first and second ICI-IA flare, with 47% of them are being expanded in the second IA flare. For PD-1hi CXCL13hi CD4+ T cells, half of the top 10 clones were shared between first and second ICI-IA flares, and 60% of shared clones were expanded in the second IA flare. Effector CD8+ T cells and PD-1hi CXCL13hi CD4+ T cells produced inflammatory cytokines including IFNg, TNFa, and IL-21, especially in the second ICI-IA. Trajectory inference analysis demonstrated that effector CD8+ T cells were positioned after tissue-resident memory T cells and effector memory T cells. The trajectory within the CD4+ T cells indicated that recently activated CD4+ T cells have the developmental potential to become PD-1hi CXCL13hi CD4+ T cells. Effector CD8+ T cells and PD-1hi CXCL13hi CD4+ T cells interact with each other and with myeloid immune cells via chemokines (CXCL9/10/11/13, CCL5) and cytokines (MIF, IL-2/7/15/21). Age-associated B cells, B cell population expanded in autoimmune diseases, were seen expanded in the second ICI-IA flare.

Conclusion: Effector CD8+ T cells and PD-1hi CXCL13hi CD4+ T cells play a pivotal role in ICI-IA disease pathogenesis. These cells were more clonally expanded and produced more inflammatory cytokines in the second ICI-IA flare, implying immune memory responses. Understanding of these cells will shed light on therapeutic targets for ICI-IA and biomarkers to predict development or recurrence of ICI-IA, an emerging disease entity in rheumatology and oncology.  

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effector-cd8-t-cells-and-pd-1hi-cxcl13hi-cd4-t-cells-contribute-to-recurrent-immune-checkpoint-inhibitor-mediated-inflammatory-arthritis/