{
  "abstract": "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.",
  "authors": [
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Hairu Yang"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Michaela Dungan"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Bhoomi Madhu"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Keely Beyries"
    },
    {
      "affiliations": [
        "Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Xin Wang"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Robert Kilpatrick"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Baron Chen"
    },
    {
      "affiliations": [
        "Tuberculosis Research Section, LCIM, NIAID, NIH, Bethesda, Maryland, USA"
      ],
      "name": "Sangmi Oh"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Marissa Berkowitz"
    },
    {
      "affiliations": [
        "Center for Single Cell Biology, Children’s Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA"
      ],
      "name": "David Smith"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Chaoting Zhou"
    },
    {
      "affiliations": [
        "Department of Pathology, New York University School of Medicine, New York, New York, USA"
      ],
      "name": "Sergei B Koralov"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, NYU Grossman School of Medicine, New York, New York, USA"
      ],
      "name": "Jordan Axelrad"
    },
    {
      "affiliations": [
        "Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Christopher J Lengner"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Nicole Belle"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Meenakshi Bewtra"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA",
        "King Center for Lynch Syndrome, University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Bryson W Katona"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA",
        "Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Ken Cadwell"
    }
  ],
  "title": "MAIT cell enrichment in Lynch syndrome is associated with immune surveillance and colorectal cancer risk",
  "uid": "a04c1cc3-65bf-5fcb-a03b-02140a0b4160"
}