The role of tissue-resident T cells in osteoarthritis during the transition to inflammatory arthritis induced by immune checkpoint inhibitors

About This Grant

PROJECT ABSTRACT OsteoarthriƟs (OA) is the most prevalent joint disease. Once viewed as an irreversible, age-related degeneraƟve change to carƟlage, OA is now recognized as a systemic disorder featuring a prominent inflammatory aspect in which T cells appear to play a role. However, the impact of OA on the development of untoward responses to various immune-modifying therapies is largely unexplored. T cell immune checkpoint inhibitors (ICIs) have revoluƟonized cancer treatment, with approximately one million cases qualifying each year. ICI anƟbodies (Abs) have demonstrated clinical effecƟveness, as shown by tumor regression and improved survival rates. However, two major drawbacks limit their applicaƟon. Firstly, tumor control is not uniform and unpredictable. Secondly, the emergence of inflammatory autoimmune toxiciƟes, referred to as immune-related adverse events (irAEs), poses substanƟal challenges. Over half of paƟents treated with ICIs experience irAE syndromes, which are marked by various paƩerns of organ inflammaƟon. We have focused on one chronic irAE, arthriƟs, which affects 37,742 Americans annually. This condiƟon can lead to the terminaƟon of essenƟal cancer therapies and results in lasƟng morbidity. The mechanisms driving irAE-arthriƟs are primarily unknown, creaƟng an urgent need for specific treatments to inhibit joint inflammaƟon while boosƟng the inflammatory tumor response. To address this, we established an irAE-arthriƟs clinic, where we found that paƟents with OA are significantly more prone to develop irAE-arthriƟs when undergoing ICI treatment than matched individuals without OA. Our research into the immunophenotype of OA synovial fluid showed most CD8 and CD4 T cells displayed a Ɵssue-resident memory (TRM) phenotype and, unexpectedly, had elevated levels of the immune checkpoint PD-1. This led us to our central hypothesis that immunoreacƟve proteins produced by mechanically stressed OA carƟlage insƟgate a localized, self-limiƟng autoreacƟve T cell response. PD-1 and the ensuing PD-1 negaƟve signaling curb this T cell-mediated Ɵssue damage, resulƟng in synovial tolerized TRM. However, ICI therapy interrupts PD-1 mediated inhibiƟon, prompƟng TRM cells to convert into effector T cells (TEFF), which drive irAE-arthriƟs. We will test this hypothesis and elucidate the mechanism through which TRM cells facilitate the transiƟon from OA to irAE-arthriƟs aŌer ICI treatment. Aim 1: To invesƟgate the hypothesis that ICIs convert OA PD-1+ TRM cells into TEFF cells, contribuƟng to Ɵssue inflammaƟon and irAE arthriƟs. We will conduct a longitudinal validaƟon study to idenƟfy phenotypes and specific lineages of T cell subsets emerging in OA and irAE joints. By tracing clonotypic TCR profiles, we will assess the extent to which TEFF in irAE joints arise directly from OA PD-1+ TRM cells or from infiltraƟng T cells. Aim 2: To characterize dendriƟc cell (DC) populaƟons in OA and irAE arthriƟs using single-cell RNA sequencing and predict cell interacƟon pathways. To explore the disƟnct funcƟons of DC in OA compared to irAE joints, we will uƟlize transcriptomic data to analyze DC populaƟons in both OA and irAE fluid. Aim 3: To employ spaƟal biology and transcriptomics to confirm the hypothesis that TEFF cells engage with immunogenic DC in irAE arthriƟs. ExtracƟng single cells from Ɵssue results in the loss of spaƟal context. To overcome this and integrate the findings from aims 1 and 2, we will apply spaƟal transcriptomics to represent the components in inflamed joints visually.