1. Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis.
- Author
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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, Fernandes RA, Koohy H, and Simmons A
- Subjects
- Humans, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes metabolism, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory drug effects, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes metabolism, Animals, Intestinal Mucosa metabolism, Intestinal Mucosa immunology, Intestinal Mucosa pathology, Intestinal Mucosa drug effects, Interferon-gamma metabolism, Female, Single-Cell Analysis, Mice, Colitis chemically induced, Colitis immunology, Colitis pathology, Immune Checkpoint Inhibitors adverse effects, Immune Checkpoint Inhibitors pharmacology
- Abstract
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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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