Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis (Q10676)

Abstract Therapeutic immune checkpoint blockade has revolutionized oncology, but treatments are limited by immune-related adverse events, including checkpoint inhibitor colitis (irColitis). To define molecular drivers of irColitis, we profiled ~300,000 cells from the colon mucosa and blood of 29 patients and controls. Patients with irColitis showed expanded mucosal Tregs, ITGAEHiCD8 tissue-resident memory T cells expressingCXCL13and Th17 gene programs, and circulatingITGB2HiCD8 T cells recruited by ICAM and CXCR3 ligands. CytotoxicGNLYHiCD4 T cells,ITGB2Hi CD8 T cells from circulation, and endothelial cells associated with hypoxia gene programs were further expanded in colitis associated with anti-PD-1/CTLA-4 compared to anti-PD-1 therapy. Luminal epithelial cells in irColitis patients expressed PD-L1 and interferon-induced signatures associated with apoptosis, increased cell turnover, and malabsorption. Together, we highlight novel roles for circulating T cells and epithelial-immune crosstalk critical to PD-1/CTLA-4-dependent tolerance and barrier function and nominate novel irColitis therapeutic targets. --- This Zenodo page provides download links for the code we developed for the analysis and the website, as well as the files containing analysis results. To get started, download the zip file shown below. For analysis results, look for the analysis/output folder and read our tutorial for how to access the expression data in R and Python. The v3 release adds cell cluster marker data for Luoma CD4 T cells and Luoma CD8 T cells to the file analysis/output/de-ova.tsv.gz.