Yang Hairu, Dungan Michaela, Beyries Keely, Wang Xin, Kilpatrick Robert, Chen Baron, Oh Sangmi, Berkowitz Marissa, Smith David, Koralov Sergei B, Axelrad Jordan, Lengner Christopher J, Belle Nicole, Bewtra Meenakshi, Katona Bryson W, Cadwell Ken
Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, 19104, USA.
bioRxiv. 2025 Aug 27:2025.08.22.671764. doi: 10.1101/2025.08.22.671764.
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 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.
林奇综合征（LS）中与结直肠癌（CRC）风险升高相关的组织微环境特征尚不明确。我们应用多模态单细胞测序平台ExCITE-seq来定义有或无CRC病史的LS携带者与一般人群对照的结肠细胞组成和转录组。我们的分析揭示了LS中广泛的重塑，包括上皮干细胞和祖细胞的显著扩增，以及成纤维细胞群体的丧失。虽然克隆扩增和终末耗竭的CD8 T细胞在有CRC病史的个体中更为突出，但无CRC的LS携带者表现出与上皮祖细胞中表达相关的细胞毒性黏膜相关恒定T（MAIT）细胞富集，这通过包括在CRC小鼠模型中证明保护功能在内的正交技术得到验证。这些发现突出了区分LS携带者的细胞特征，并提示MAIT细胞在人类CRC监测中的保护作用。
