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

Journal article

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.

Authors: Gupta, T; Antanaviciute, A; Lee, CH-J; Ottakandathil Babu, R; Aulicino, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Cancer Cell
• Volume: 42
• Issue: 5
• Pages: 797-814
• Publication date: 2024-05-13
• Acceptance date: 2024-04-17
• DOI: 10.1016/j.ccell.2024.04.010
• EISSN: 1878-3686
• ISSN: 1535-6108
• Pmid: 38744246
• Language: English