Background/Purpose: Monoclonal antibodies against CTLA-4 and PD-1 have revolutionized the field of immuno-oncology over the past decade. These therapies however are limited by immune related adverse events (irAEs) that can affect nearly every organ system. Inflammatory arthritis (irIA) is a common well-recognized irAE, but with a poorly understood pathophysiology that results in limited targeted treatments. Mechanistic insight into disease pathogenesis has been hampered by the lack of animal models, as mice treated with these drugs do not develop significant irAEs. We thus designed a translational study using human samples focused on identifying distinct cells types, and critical signaling pathways involved in promoting irIA.

Methods: We have established a specialty clinic that provides comprehensive clinical evaluation and long-term follow up of patients with suspected rheumatological irAEs. This clinic also enables serial sample collection of synovial fluid and matched blood samples at the time of the patient’s first rheumatologic assessment and, when possible, serially before and after the initiation of immunosuppressive therapy. To define distinct cell populations that might be driving irIA pathogenesis and could be used as a diagnostic marker, we leveraged 10X Genomics droplet-based single-cell RNA-sequencing strategies that do not require an a prioriknowledge of the specific cell populations or signaling components involved. Single-cell TCR analysis was performed in parallel on the same samples using the VDJ enrichment strategy.

Results: Approximately, 25,000 single cells from the synovial fluid of 5 patients with different irIA clinical phenotypes were analyzed. Findings shows that synovial fluid is highly heterogenous in composition and includes diverse populations of myeloid and dendritic cells in high proportions. Furthermore, distinct CD8+ cytotoxic T cells across disease phenotypes were expanded. Paralleled single T cell receptor analyses identified diverse clonotypes within these expanded lymphocyte subsets, as well as clonotypic expansion within specific cytotoxic CD8+ populations across patients.

Conclusion: Our systems-level approach provides a better understanding of the biological basis of irIA. Importantly, because irIA provides a model to study mechanisms of immune-tolerance, we believe that our translational effort also represents a unique opportunity to study proximate events leading to autoimmunity in humans.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterizing-arthritis-related-to-immune-checkpoint-inhibitors-using-synovial-fluid-and-matched-blood/