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

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<0.001). Using mIF three immune cell density clusters were identified; 1) high T cell density, low macrophage density, 2) low T cell density, low macrophage density, and 3) high T cell, macrophage and SMA density, with significant differences in future lesion risk (Cluster 1: 22%, Cluster 2: 41%, Cluster 3: 36%, p=0.032). Bulk RNAseq and spatial transcriptomic analysis revealed significant variation in T cell and macrophage co-location and gene expression profiles between clusters. Conclusion Adenoma immune contexture emerges as a possible determinant of future metachronous lesion risk, offering a novel biomarker to refine surveillance.