Elucidation of mechanisms underlying inflammatory arthritis induced by immune checkpoint inhibitors

The National Institutes of Health Office of the Director awarded Yale University $300,000 on September 5, 2026, under the Trans-NIH Research Support program (CFDA 93.310) to investigate the mechanisms by which immune checkpoint inhibitors trigger inflammatory arthritis.

The funded research addresses a clinical gap in managing immune-related adverse events caused by PD-1 inhibitors used in cancer treatment. Inflammatory arthritis induced by these inhibitors currently requires steroid immunosuppression, which reduces cancer therapy efficacy. The investigator team has identified clonally expanded CXCR3-positive CD8+ T cells in synovial fluid of affected patients and developed a murine model that recapitulates human disease. Research Aim 1 will characterize the cellular, molecular, and epigenetic properties of tissue-resident memory-like cells in joints and collagen II–draining lymph nodes, define their activation kinetics, and elucidate the mechanism by which PD-1 inhibition mediates their in vitro activation. Aim 2 will determine whether these cells are sufficient to induce arthritis and identify therapeutic targets.

Work is performed at Yale University in New Haven, Connecticut. The award period runs from September 5, 2026, through August 31, 2027. This is a Project Grant, the standard NIH assistance type for investigator-initiated research evaluated through peer review for scientific merit and program relevance.

Abstract

Immune checkpoint inhibitors (icis), particularly programmed cell death-1 inhibitors (PD-1I), have revolutionized cancer treatment, and PD-1I-based therapies are widely used in patients with malignancies. However, icis often cause immune-related adverse events (iraes), including inflammatory arthritis (ICI-arthritis). Steroids, the firstline irae treatment, significantly reduce ICI antitumor efficacy. Therefore, mechanism-rooted immunosuppression is critical in managing ICI-arthritis; however, its mechanism is poorly understood. We uncovered that CXCR3HI CD8+ t cells are clonally expanded in the synovial fluid (SF) of ICI-arthritis patients. Further, these cells exhibit high expression of tissue-resident memory (TRM) cell-associated molecules. In parallel, we observed that type II chicken collagen (CII)-primed mice develop DE novo inflammatory arthritis upon PD-1 inhibition (hereafter referred to as PD-1I arthritis). These mice recapitulate human PD-1I arthritis from clinical, histological, and immunological perspectives. Notably, CD69HI CD103HI CD8+ t cells, termed TRM-like cells, are expanded in the joints as well as CII-draining lymph nodes in PD-1I arthritis mice. Based on our preliminary data, we hypothesize that PD-1 inhibition breaks peripheral tolerance of intraarticular trmlike cells, inducing activation and expansion of TRM-like cells, resulting in inflammatory arthritis. In aim 1, we will assess the mechanisms by which PD-1 inhibition promotes TRM-like cell-driven arthritis using our novel PD-1I arthritis model. First, we will identify the cellular, molecular, and epigenetic characteristics of TRM-like cells in joints and CII-draining lymph nodes. Next, we will determine their kinetics, define the mechanism by which PD-1 inhibition mediates their activation in vitro. In aim 2, we will determine whether TRM-like cells are sufficient to induce inflammatory arthritis by adoptive t cell transfer experiment. This proposal is important as the results will unveil the mechanisms of PD-1I arthritis.