Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis.
Cancer Cell
; 42(5): 797-814.e15, 2024 May 13.
Article
em En
| MEDLINE
| ID: mdl-38744246
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.
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Base de dados:
MEDLINE
Assunto principal:
Colite
/
Inibidores de Checkpoint Imunológico
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article