POS0402 CLONALLY EXPANDED CD38hi CYTOTOXIC CD8 T CELLS DEFINE THE T CELL INFILTRATE IN CHECKPOINT INHIBITOR-ASSOCIATED ARTHRITIS

Abstract

BackgroundImmune checkpoint inhibitor (ICI) therapies that promote T cell activation have improved outcomes for advanced malignancies yet can also elicit harmful autoimmune reactions. The T cell mechanisms mediating these iatrogenic autoimmune events remain unclear.ObjectivesTo investigate the immunophenotype, transcriptomic feature and clonotypes of T cells from joints of patients affected by ICI-induced inflammatory arthritis (ICI-arthritis).MethodsDetailed immunophenotyping was performed on mononuclear cells from synovial fluid (SF) using mass cytometry and flow cytometry to identify significantly altered populations in ICI-A compared to seropositive rhrumatoid arthritis (RA) and psoriatic arthritis (PsA) (p<0.05). Bulk RNA-seq was performed on altered SF CD8 T cell subsets from ICI-A, RA and PsA to investigate their transcriptomic features. Cytokine profile and pathways enriched in ICI-A CD8 T cells were examined using differentially expressed genes, intracellular staining, and in vitro culture. TCR clonotypes were examined using single cell RNA-seq of T cells from synovial fluid, tissue and blood of ICI-A.ResultsCompared to the autoimmune arthritides RA and PsA, ICI-arthritis joints contained an expanded CD38hi CD127- CD8+ T cell subset that displays cytotoxic, effector, and interferon (IFN) response signatures. Exposure of synovial T cells to Type I IFN, more so than IFN-γ, induced the CD38hi cytotoxic phenotype. Single cell transcriptomic and T cell repertoire (TCR) analyses indicated that the abundance of CD38hi CD8 T cells in ICI-arthritis resulted from proliferation of a limited number of clones. The CD38hi population appeared distinct from dysfunctional T cells and clonally most related to TCF7+ memory populations. Comparison of synovial tissue from bilateral knees of the same patient demonstrated considerable sharing of TCR clonotypes among CD38hi CD8 T cells between the two joints. Further, TCR clonotypes expanded in synovial fluid of ICI-arthritis patients were detected in circulating T cells, and circulating CD38hi CD8 T cells are also expanded in ICI-arthritis patients.ConclusionThese results define a distinct CD8 T cell subset in the synovial fluid and in the circulation of patients with ICI-A that may be directly activated by ICI therapy to mediate a tissue-specific autoimmune response.Disclosure of InterestsNone declared.