Project description:Checkpoint inhibitor colitis (CPI colitis) is a frequent immune-related adverse event resulting from cancer immunotherapy that is currently treated with empiric immunosuppression such as corticosteroids. A greater understanding of the pathogenesis of CPI colitis in the steroid-refractory setting is required to develop better colitis interventions targeted to each patient. Using paired colon biopsies and blood from steroid-experienced patients with endoscopically confirmed CPI colitis, combined with control patients, we performed multiplexed single-cell transcriptomics (scRNA/TCRseq) and proteomics (CITEseq, CyTOF) to identify contributing immune and non-immune populations. In CPI colitis patient biopsies compared to healthy controls, we found enrichment of resident memory (RM) T cells in both the CD8+ and unexpectedly the CD4+ compartments, as well as cytotoxic CD8+ T cells. These 3 populations expressed exact matching TCR, suggesting that CD4+ RM and CD8+ RM T cells are clonal progenitors that give rise to tissue-destructive cytotoxic effectors. Unbiased CyTOF and confirmatory scRNAseq and CITEseq analysis identifies specific mobilized subpopulations of both cytotoxic CD8+ and CD4+ RM cells that express both activation markers CD38 and HLA-DR, underscoring their pathogenic potential. CPI colitis induces global upregulation of interferon signaling and antigen presentation, as well as epithelial-specific dysregulation of homeostatic pathways (aquaporin/solute transporters) which is shared with ulcerative colitis. However, distinct from ulcerative colitis, CPI colitis involves specific alterations in stromal cell metabolic (NAD+, tryptophan) or extracellular signaling (BMP) pathways that directly impact epithelial cell survival, arguing for distinct therapeutic targeting. Finally, endothelial cells in CPI colitis demonstrate enrichment of the integrin 47 ligand MADCAM-1 (which is targeted by anti-47 antibody vedolizumab to treat colitis). This ligand is enriched in CPI colitis patients who received TNF blockade and anti-CTLA-4, identifying subsets of patients who may be more responsive to vedolizumab treatment. This work identifies putative pathogenic resident memory and cytotoxic T cells, and non-immune stromal and endothelial populations, whose properties may nominate subsets of CPI colitis patients amenable to distinct targeting strategies.

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Transcriptomic profiling of the role of Ctla4 in the innate immune system

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