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

MAIT cell enrichment in Lynch syndrome is associated with immune surveillance and colorectal cancer risk | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article MAIT cell enrichment in Lynch syndrome is associated with immune surveillance and colorectal cancer risk Ken Cadwell, Hairu Yang, Michaela Dungan, Keely Beyries, Xin Wang, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7273425/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Tissue microenvironment characteristics associated with elevated risk of colorectal cancer (CRC) in Lynch syndrome (LS) are poorly characterized. We applied the multimodal single cell sequencing platform ExCITE-seq to define the colonic cellular composition and transcriptome of LS carriers with and without a history of CRC compared with general population controls. Our analysis revealed widespread remodeling in LS that included striking expansion of epithelial stem and progenitor cells, and loss of fibroblast populations. 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. These findings highlight cellular features that distinguish LS carriers and suggest a protective role of MAIT cells in human CRC surveillance. Biological sciences/Cancer/Tumour immunology/Immunosurveillance Health sciences/Oncology/Cancer/Tumour immunology Lynch syndrome Colorectal cancer Epithelial stem and progenitor cells fibroblasts MAIT cells Full Text Additional Declarations Yes there is potential Competing Interest. B.K. has received clinical research funding paid to the institution from Janssen, Immunovia, Freenome, Guardant, Epigenomics, Universal Diagnostics, and Recursion. B.K. is an advisory board member at Immunovia. K.C. has received research funding from Pfizer, Takeda, Pacific Biosciences, Genentech and Abbvie. K.C. has consulted for or received an honorarium for speaking engagement from Puretech Health, Genentech, Moderna, Gentibio, and Abbvie. K.C. is an inventor on US patent 10,722,600 and provisional patents 62/935,035 and 63/157,225. J.A. has received research grants from BioFire Diagnostics, Genentech, Janssen, and Takeda; consultancy fees, honorarium, or advisory board fees from Abbvie, Abivax, Adiso, Biomerieux, Bristol-Myers Squibb, Celltrion, Ferring, Fresenius, Janssen, Merck, Pfizer, Sanofi, Takeda, and Vedanta. Supplementary Files LynchMAITSupplementalFiguresS1S10.pdf LynchMAIT_SupplementalFiguresS1-S10 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7273425","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":504117548,"identity":"9f216b0e-7e93-4f4d-a3f4-38f5dedc6972","order_by":0,"name":"Ken 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We applied the multimodal single cell sequencing platform ExCITE-seq to define the colonic cellular composition and transcriptome of LS carriers with and without a history of CRC compared with general population controls. Our analysis revealed widespread remodeling in LS that included striking expansion of epithelial stem and progenitor cells, and loss of fibroblast populations. 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. 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