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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.

Original publication

DOI

10.1016/j.ccell.2024.04.010

Type

Journal article

Journal

Cancer Cell

Publication Date

13/05/2024

Volume

42

Pages

797 - 814.e15

Keywords

cancer immunotherapy, checkpoint colitis, scRNA-Seq, spatial transcriptomics, ulcerative colitis, Colitis, Immune Checkpoint Inhibitors, Humans, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, CD4-Positive T-Lymphocytes, Animals, Intestinal Mucosa, Interferon-gamma, Female, Single-Cell Analysis, Mice