Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis.
Gupta T., Antanaviciute A., Hyun-Jung Lee C., Ottakandathil Babu R., Aulicino A., Christoforidou Z., Siejka-Zielinska P., O'Brien-Ball C., Chen H., Fawkner-Corbett D., Geros AS., Bridges E., McGregor C., Cianci N., Fryer E., Alham NK., Jagielowicz M., Santos AM., Fellermeyer M., Davis SJ., Parikh K., Cheung V., Al-Hillawi L., Sasson S., Slevin S., Brain O., TIP Consortium None., Fernandes RA., Koohy H., Simmons A.
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.