MAIT cell enrichment in Lynch syndrome is associated with immune surveillance and colorectal cancer risk

Background Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC) and results from pathogenic germline variants affecting mismatch repair. The tissue microenvironment that contributes to this elevated risk of CRC is poorly characterised particularly during the early precancerous stages.Objective To define features of the colonic microenvironment that distinguish LS carriers with and without a history of CRC from one another and from the general population.Design We applied Expanded Cellular Indexing of Transcriptomes and Epitopes by sequencing, a multimodal single-cell platform, to profile tumour-free colonic cellular composition and transcriptome of LS carriers with and without a history of CRC compared with general population controls. We used flow cytometry, histology and mouse modelling to validate key observations.Results We observed widespread remodelling in LS that included striking expansion of epithelial stem and progenitor cells, loss of fibroblast populations and changes in lymphocyte subsets. Although clonally expanded and terminally exhausted CD8 T cells were more prominent in individuals with a history of CRC, LS carriers without CRC displayed enrichment of cytotoxic mucosal-associated invariant T (MAIT) cells associated with CCL20 expression in epithelial progenitors, validated by orthogonal techniques including demonstration of a protective function in a murine model of CRC.Conclusions These findings define key features of the LS colonic microenvironment and suggest that MAIT cell enrichment contributes to immune surveillance against CRC, offering new insights into disease penetrance, risk stratification and prevention.