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., Bird-Lieberman E., Fourie S., Johnston R., Joshi H., Mujamdar D., Panter S., Patodi N., Shaji S., Tidbury J., Verma A., 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.