<p>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 colonic mucosa and blood of 29 patients and controls. Patients with irColitis showed expanded mucosal Tregs (regulatory T cells), CD8 tissue-resident memory T cells expressing <a href="https://www.ncbi.nlm.nih.gov/gene/10563/">CXCL13 </a>and Th17 gene programs, and recirculating <a href="https://www.ncbi.nlm.nih.gov/gene/3689">ITGB2</a> CD8 T cells. Cytotoxic CD4 T cells, recirculating CD8 T cells, and endothelial cells expressing hypoxia gene programs were further expanded in colitis associated with anti-<a href="https://www.ncbi.nlm.nih.gov/gene/5133">PD-1</a>/<a href="https://www.ncbi.nlm.nih.gov/gene/1493">CTLA-4</a> compared to in the presence of anti-PD-1 therapy. Luminal epithelial cells in irColitis patients expressed <a href="https://www.ncbi.nlm.nih.gov/gene/255738">PCSK9</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/29126">PD-L1</a>, and interferon-induced signatures associated with apoptosis, increased cell turnover, and malabsorption.</p><p>Raw data files from both colon and PBMCs from irColitis patients and controls have been provided to dbGaP. Count matrices derived from raw RNA-Seq data will be available through GEO accession <a href="https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE206301">GSE206301</a>.</p>

Altered Interactions between Circulating and Tissue-Resident CD8 T Cells with the Colonic Mucosa Define Checkpoint Inhibitor Colitis