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

BackgroundCurrent 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. MethodsPatients undergoing polypectomy within the Scottish Bowel Screening Programme, with surveillance colonoscopy between 6 months and 6 years were included. Chromogenic immunohistochemistry (IHC; n=2642), 6-plex multiplex immunofluorescence (mIF; n=334), 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. ResultsAfter adjustment for age, sex, site, size and dysplasia, adenoma CD3+ T cell density was significantly associated with future colorectal neoplasia (HR 1.43, 95% CI 1.19-1.71, 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. ConclusionAdenoma immune contexture emerges as a determinant of future metachronous lesion risk, offering a novel biomarker to refine surveillance and reduce disease burden. SummaryWhat is already known on this topic: O_LIPost-polypectomy surveillance is currently recommended to patients with high-risk pathological features to detect metachronous lesions and cancer. However current guidelines misclassify risk in a proportion of patients, leading to unnecessary surveillance for some, whilst falsely reassuring others. C_LI What this study adds: O_LIAnalysis of this large post-polypectomy surveillance cohort reveals that adaptive immune responses within removed index adenomas predicts low risk of metachronous lesions, while an immune excluded phenotype signals higher risk, independent of pathological characteristics, and patient risk factors. C_LI How this study might affect research, practice or policy: O_LIDefining immune cell spatial distributions and interactions that drive future adenoma and cancer risk will enable more precise risk stratification for surveillance, informing surveillance guidelines and shaping targeted colorectal cancer prevention strategies. C_LI