Background/Purpose:

Checkpoint inhibitors (ICIs) are revolutionizing cancer treatment; however, ICI therapy is associated with immune-related adverse events (irAEs). irAEs can be life-threatening and/or severely impair quality of life, necessitating early termination of ICI treatment. Two percent of cancer patients who receive ICI treatment develop arthritis as an irAE (arthritis-irAE). Prompt diagnosis and early intervention are critical in the management of irAE; however, detailed characterization of immune cells in the inflamed tissues, the first step in elucidating the mechanisms of irAEs, is still lacking. Here, we characterize synovial immune cells isolated from patients with arthritis-irAE.

Methods:

We analyzed synovial fluid from five patients with arthritis-irAE. As a control, we also analyzed one anonymous pediatric tonsil. We stained lymphoid immune cells with lineage-specific markers and measured effector cytokines in the CD4⁺ T cell populations.

Results:

Arthritis developed an average of 270±375 days after the first ICI infusion. Two of the five patients developed arthritis after completion of ICI treatment. Arthritis was treated with systemic prednisone and/or local injection. Three patients achieved complete resolution of arthritis (“steroid responders”) while two patients had suboptimal response and needed additional treatment (“steroid non-responders”). The most abundant lymphoid immune cells were CD4⁺ T cells (53.1±13.2% of live immune cells), followed by CD8⁺ T cells, NK cells, γδ T cells, NK T cells, and B cells. Most CD8⁺ T cells were effector memory or terminally differentiated effector memory cells. All CD4⁺ T cell subsets were identified in the synovial fluid, including regulatory T cells (Treg), naïve T cells, Th1 (CXCR3^hi CCR6^hi), Th1.17 (CXCR3^hi CCR6^hi), Th17 (CXCR3^lo CCR6^hi), and follicular helper T cells (CXCR5⁺). Effector CD4⁺ T cell cytokines, including interferon gamma, IL-4, IL-17, and IL-21, were produced by both Tregs and non-Tregs. Interestingly, IL-17⁺ non-Treg cells were expanded in steroid non-responders compared to steroid responders, indicating that Th17 cells might play a critical role in persistent arthritis-irAE.

Conclusion:

Our results suggest that arthritis-irAE can develop at any time during or after the ICI treatment. The observed expansion of IL-17⁺ non-Treg cells in synovial fluid from steroid non-responders suggests that Th17 cells might play a key role in the pathogenesis of arthritis-irAE. Understanding of Th17 CD4⁺ cell biology will provide therapeutic targets and reliable biomarkers for arthritis-irAEs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterization-of-lymphoid-cells-in-synovial-fluid-from-cancer-patients-with-immunotherapy-induced-arthritis/