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

Semir Beyaz; Charlie Chung; Haiwei Mou; Khristian E Bauer-Rowe; Michael E Xifaras; Ilgin Ergin; Lenka Dohnalova; Moshe Biton; Karthik Shekhar; Onur Eskiocak; Katherine Papciak; Kadir Ozler; Mohammad Almeqdadi; Brian Yueh; Miriam Fein; Damodaran Annamalai; Eider Valle-Encinas; Aysegul Erdemir; Karoline Dogum; Vyom Shah; Aybuke Alici-Garipcan; Hannah V Meyer; Deniz M Özata; Eran Elinav; Alper Kucukural; Pawan Kumar; Jeremy P McAleer; James G Fox; Christoph A Thaiss; Aviv Regev; Jatin Roper; Stuart H Orkin; Ömer H Yilmaz

doi:10.1016/j.stem.2021.08.007

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.

Authors

Semir Beyaz¹, Charlie Chung², Haiwei Mou², Khristian E Bauer-Rowe³, Michael E Xifaras⁴, Ilgin Ergin², Lenka Dohnalova⁵, Moshe Biton⁶, Karthik Shekhar⁷, Onur Eskiocak², Katherine Papciak², Kadir Ozler², Mohammad Almeqdadi³, Brian Yueh², Miriam Fein², Damodaran Annamalai⁸, Eider Valle-Encinas³, Aysegul Erdemir³, Karoline Dogum³, Vyom Shah², Aybuke Alici-Garipcan², Hannah V Meyer², Deniz M Özata⁹, Eran Elinav¹⁰, Alper Kucukural¹¹, Pawan Kumar¹², Jeremy P McAleer¹³, James G Fox⁸, Christoph A Thaiss⁵, Aviv Regev¹⁴, Jatin Roper¹⁵, Stuart H Orkin¹⁶, Ömer H Yilmaz¹⁷

Affiliations

¹ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA. Electronic address: beyaz@cshl.edu.
² Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
³ The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA.
⁴ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA.
⁵ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; The Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel.
⁷ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Chemical and Biomolecular Engineering, Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA.
⁸ Division of Comparative Medicine, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁹ RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
¹⁰ Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.
¹¹ Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
¹² Department of Microbiology and Immunology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
¹³ Department of Pharmaceutical Science and Research, Marshall University School of Pharmacy, Huntington, WV 25701, USA.
¹⁴ The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02140, USA.
¹⁵ Department of Medicine, Division of Gastroenterology, Duke University, Durham, NC 27710, USA.
¹⁶ Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: stuart_orkin@dfci.harvard.edu.
¹⁷ The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: ohyilmaz@mit.edu.

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 (IFNγ) 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Carcinogenesis
Diet, High-Fat
Epithelial Cells
Histocompatibility Antigens Class II*
Humans
Intestines*

Substances

Histocompatibility Antigens Class II

Abstract

Publication types

MeSH terms

Substances

Grants and funding