Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis

The success of checkpoint inhibitors (CPIs) for cancer has been tempered by immune-related adverse effects including colitis. CPI-induced colitis is hallmarked by expansion of resident mucosal IFNγ cytotoxic CD8+ T cells, but how these arise is unclear. Here, we track CPI-bound T cells in intestinal tissue using multimodal single-cell and subcellular spatial transcriptomics (ST). Target occupancy was increased in inflamed tissue, with drug-bound T cells located in distinct microdomains distinguished by specific intercellular signaling and transcriptional gradients. CPI-bound cells were largely CD4+ T cells, including enrichment in CPI-bound peripheral helper, follicular helper, and regulatory T cells. IFNγ CD8+ T cells emerged from both tissue-resident memory (TRM) and peripheral populations, displayed more restricted target occupancy profiles, and co-localized with damaged epithelial microdomains lacking effective regulatory cues. Our multimodal analysis identifies causal pathways and constitutes a resource to inform novel preventive strategies. [Display omitted] •Multi-modal scRNA-seq and ST atlas incorporating CPI-bound T cell tracking•Identified CD4+ (Tfh, Tph, Th17, Tregs) and CD8+ (HAVCR2+) T cells bound by CPI•Increased CPI-bound T cells in distinct tissue niches in patients with CPI-colitis•Colonic cellular microdomain composition differentiates CPI-colitis from UC Gupta et al. track checkpoint inhibitor (CPI)-bound T cells utilizing scRNA-seq and subcellular spatial transcriptomics in blood and intestinal tissue, defining distinct T cell subtypes and tissue niches linked to colitis development. They define the pathogenic cellular microdomains differentiating CPI-colitis from ulcerative colitis (UC).