UMass Chan Medical School Faculty Publications

Title

Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis

UMMS Affiliation

RNA Therapeutics Institute; Program in Molecular Medicine

Publication Date

2021-11-04

Document Type

Article

Disciplines

Cancer Biology | Cell Biology | Cellular and Molecular Physiology

Abstract

Little is known about how interactions of diet, intestinal stem cells (ISCs), and immune cells affect early-stage intestinal tumorigenesis. We show that a high-fat diet (HFD) reduces the expression of the major histocompatibility complex class II (MHC class II) genes in intestinal epithelial cells, including ISCs. This decline in epithelial MHC class II expression in a HFD correlates with reduced intestinal microbiome diversity. Microbial community transfer experiments suggest that epithelial MHC class II expression is regulated by intestinal flora. Mechanistically, pattern recognition receptor (PRR) and interferon-gamma (IFNgamma) signaling regulates epithelial MHC class II expression. MHC class II-negative (MHC-II-) ISCs exhibit greater tumor-initiating capacity than their MHC class II-positive (MHC-II+) counterparts upon loss of the tumor suppressor Apc coupled with a HFD, suggesting a role for epithelial MHC class II-mediated immune surveillance in suppressing tumorigenesis. ISC-specific genetic ablation of MHC class II increases tumor burden cell autonomously. Thus, HFD perturbs a microbiome-stem cell-immune cell interaction that contributes to tumor initiation in the intestine.

Keywords

MHC-II, antigen presentation, cancer, diet, high-fat diet, intestinal stem cells, microbiome, obesity

DOI of Published Version

10.1016/j.stem.2021.08.007

Source

Beyaz S, Chung C, Mou H, Bauer-Rowe KE, Xifaras ME, Ergin I, Dohnalova L, Biton M, Shekhar K, Eskiocak O, Papciak K, Ozler K, Almeqdadi M, Yueh B, Fein M, Annamalai D, Valle-Encinas E, Erdemir A, Dogum K, Shah V, Alici-Garipcan A, Meyer HV, Özata DM, Elinav E, Kucukural A, Kumar P, McAleer JP, Fox JG, Thaiss CA, Regev A, Roper J, Orkin SH, Yilmaz ÖH. Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis. Cell Stem Cell. 2021 Nov 4;28(11):1922-1935.e5. doi: 10.1016/j.stem.2021.08.007. Epub 2021 Sep 15. PMID: 34529935; PMCID: PMC8650761. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Cell stem cell

PubMed ID

34529935

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