Novel adenoma-immune phenotypes are associated with risk of metachronous polyps and colorectal cancer in a bowel screening cohort

Abstract Background Current British Society of Gastroenterology (BSG) guidelines misclassify metachronous lesion risk after polypectomy in approximately 40% of patients. Building on evidence that immune exclusion drives progression of adenomas to colorectal cancer, this study examined immune profiles in screen-detected adenomas as a predictive biomarker for metachronous lesion risk. Methods Patients undergoing polypectomy within the Scottish Bowel Screening Programme, with surveillance colonoscopy between 6 months and 6 years were included (n=2642). Chromogenic immunohistochemistry (IHC; n=2466), 6-plex multiplex immunofluorescence (mIF; n=331), and spatially resolved 6000-plex single cell transcriptomics (n=7) were applied to adenoma microarrays. Cell density and location were measured using QuPath. Hierarchical then K-means clustering was used to define immune cell density-based clusters, which were compared to future lesion events using Kaplan-Meier curves and the log rank test. Results After adjustment for age, sex, site, size and dysplasia, adenoma CD3 + T cell density was significantly associated with future colorectal neoplasia (OR 1.44, 95% CI 1.20-1.72, p