Year: 2026
Type: conference-abstract
Abstract: Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but can trigger immune-related adverse events such as colitis. The mechanisms driving ICI-induced intestinal inflammation remain poorly understood, limiting the development of targeted therapeutic strategies.Methods We analyzed colon biopsies from a cohort of 23 patients with or without ICI-induced colitis at the University of Chicago using integrated single-cell RNA sequencing and paired spatial transcriptomics and proteomics. To further contextualize our findings, we performed a meta-analysis across five independent patient datasets, including our own cohort. 1–4 To validate findings mechanistically, we developed a new mouse model of ICI colitis using LCMV Armstrong infection to establish the causal role of intestinal CD8+ tissue-resident memory T cells (TRMs), followed by adoptive transfer of antigen-specific P14 cells and ICI treatment to provoke colonic inflammation. Treg contribution was assessed using Foxp3-DTR mice with diphtheria toxin-mediated depletion.Results Transcriptomic mapping of patient biopsies revealed accumulation of proliferative cytotoxic T cells in the colon, alongside Treg dysfunction characterized by upregulation of Th1- and IFN-response genes including IL12RB2, IFI6, and CXCL9, a signature distinct from Th17-driven inflammatory bowel disease. Single-cell and TCR analyses identified CD8 + TRMs as key cellular targets of ICIs, displaying a cytotoxic profile enriched for granzymes, chemokines, and effector transcriptional modules. Spatial transcriptomics and proteomics revealed two distinct tissue niches within the inflamed colon: an immune hub characterized by co-localization of macrophages, T cells, and Tregs, and an epithelial apoptotic niche marked by active epithelial cell death – findings that implicate both immune dysregulation and direct epithelial injury as spatial features of ICI colitis. In our mouse model, ICI treatment following LCMV-induced TRM establishment provoked intestinal inflammation, recapitulating the phenotype observed in human disease. Treg depletion exacerbated colitis severity, supporting a role for Treg dysfunction in amplifying TRM-driven pathology.Conclusions These findings define a pathogenic circuit in which CD8 + TRM reactivation, Treg destabilization, and Th1-skewed inflammation converge to drive ICI-induced colitis. This mechanistic framework advances our understanding of ICI-associated autoimmunity and may inform the development of targeted interventions that limit intestinal toxicity while preserving antitumor immunity.References Gupta T, Aulicino A, Christoforidou Z, et al. Tracking in situ checkpoint inhibitor-bound T cells in patients with checkpoint-induced colitis. Cancer Cell 2024;42(5):797-814.Thomas MF, Slowikowski K, Manakongtreecheep K, et al. Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis. Nat Med. 2024;30(5):1349-1362.Luoma AM, Suo S, Williams HL, et al. Molecular pathways of colon inflammation induced by cancer immunotherapy. Cell 2020;182(3):655-671.He JY, Kim YJ, Mennillo E, et al. Dysregulation of CD4+ and CD8+ resident memory T, myeloid, and stromal cells in steroid-experienced checkpoint inhibitor colitis. J Immunother Cancer. 2024;12(4).
Institution: University of Chicago
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225166947