Spatial landscapes of immune checkpoint inhibitor-induced colitis

Immune-related adverse events (irAEs) compromise the effective use of immune checkpoint inhibitors (ICIs). Although CD8+ T cell overactivation is central to anti-PD-1-related irAEs, the local immunological mechanisms contributing to colitic irAEs remain poorly understood. We collected colonic tissue samples from patients with and without colitic irAE following anti-PD-1 treatment. Integrating spatial transcriptomics with comprehensive computational analysis, we examined the local transcriptional profiles enriched with CD8+ T cell infiltration in colitic irAE. Integrated computational analysis identified ten key candidate mediators of colitic irAE, which validated in independent single-cell RNA sequencing datasets and tissue sections for representative candidates CLDN3 and TFF3. Epithelial barrier disruption and epithelial-mesenchymal transition contributed to colitic irAE pathogenesis, together with an increase in regulatory T cells, endothelial cells, fibroblasts, and macrophages. Expression of key colitic irAE regulator genes was associated with severity of adverse events and endoscopic features. Our findings indicate epithelial barrier disruption and a distinct immunological landscape in colitic irAE to inform diagnostic and therapeutic strategies.