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.

Rheumatic complications of checkpoint inhibitors: Lessons from autoimmunity

“…These T cells are activated (expressing IFNG and HAVCR2), proliferative, and are more clonal. 38,39 Phenotypically similar activated PDCD1 hi CXCL13 + CD8A + T cells have been found to be enriched in irAE-colitis, 40 again expressing high IFNG and HAVCR2 but, in contrast to those in irArthritis, also coexpressing Th17 cytokines IL17A and IL26. The same population is enriched in checkpoint inhibitor pneumonitis, again overexpressing IL17A and IFNG but also here expressing CSF2.…”

“…50,51 By contrast rheumatic irAEs such as arthritis have limited B cell infiltration. 38,39 Labial salivary gland biopsies from irAE-induced exocrine gland dysfunction superficially share a similar pattern of lymphocytic inflammation to Sjogren's, but they are notable for the reduced or absent level of CD20 + B cells. 52 Plasma cells are present in muscle in inclusion body myositis and polymyositis, with evidence of affinity maturation with IgM to IgG isotype class switching, clonal expansion and somatic mutation within muscle.…”

Identification of outcome domains in immune checkpoint inhibitor-induced inflammatory arthritis and polymyalgia rheumatica: A scoping review by the OMERACT irAE working group

“…Treatment of such irAE often follows treatment recommendations of de novo rheumatic diseases. It is not fully known, however, how closely the pathogenesis of irAE corresponds to de novo rheumatic disease, as some publications have identified notable differences [7][8][9] .…”

Early Increase of Circulating Transitional B Cells and Autoantibodies to Joint‐Related Proteins in Patients With Metastatic Melanoma Developing Checkpoint Inhibitor–Induced Inflammatory Arthritis

“…In addition, they have been shown in patients before the onset of RA in the early stages of disease and have been associated with disease activity (16)(17)(18). Experimental data have highlighted a likely role for T cells in ICI-IA (19), but growing evidence suggests that B cells may also be affected by ICI treatment (6). However, so far, no specific data have linked B cells or autoantibody-mediated immunity to ICI-IA.…”