Dietary suppression of MHC-II expression in intestinal stem cells enhances intestinal tumorigenesis

Beyaz, S.; Roper, J.; Xifaras, M. E.; Bauer-Rowe, K. E.; Ergin, I.; Dohnalova, L.; Biton, M.; Shekar, K.; Mou, H.; Eskiocak, O.; Ozata, D. M.; Chung, C.; Papciak, K.; Almeqdadi, M.; Fein, M.; Erdemir, A.; Valle-Encinas, E.; Dogum, K.; Garipcan, A.; Meyer, H.; Fox, J. G.; Elinav, E.; Kucukural, A.; Kumar, P.; McAleer, J.; Thaiss, C. A.; Regev, A.; Orkin, S. H.; Yilmaz, O. H.

doi:10.1101/2020.09.05.284174

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bioRxiv · 10.1101/2020.09.05.284174

Dietary suppression of MHC-II expression in intestinal stem cells enhances intestinal tumorigenesis

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Abstract

Little is known about how interactions between diet, immune recognition, and intestinal stem cells (ISCs) impact the early steps of intestinal tumorigenesis. Here, we show that a high fat diet (HFD) reduces the expression of the major histocompatibility complex II (MHC-II) genes in ISCs. This decline in ISC MHC-II expression in a HFD correlates with an altered intestinal microbiome composition and is recapitulated in antibiotic treated and germ-free mice on a control diet. Mechanistically, pattern recognition receptor and IFNg signaling regulate MHC-II expression in ISCs. Although MHC-II expression on ISCs is dispensable for stem cell function in organoid cultures in vitro, upon loss of the tumor suppressor gene Apc in a HFD, MHC-II- ISCs harbor greater in vivo tumor-initiating capacity than their MHC-II+ counterparts, thus implicating a role for epithelial MHC-II in suppressing tumorigenesis. Finally, ISC-specific genetic ablation of MHC-II in engineered Apc-mediated intestinal tumor models increases tumor burden in a cell autonomous manner. These findings highlight how a HFD alters the immune recognition properties of ISCs through the regulation of MHC-II expression in a manner that could contribute to intestinal tumorigenesis.

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Beyaz, S., Roper, J., Xifaras, M. E., Bauer-Rowe, K. E., Ergin, I., Dohnalova, L., Biton, M., Shekar, K., Mou, H., Eskiocak, O., Ozata, D. M., Chung, C., Papciak, K., Almeqdadi, M., Fein, M., Erdemir, A., Valle-Encinas, E., Dogum, K., Garipcan, A., Meyer, H., Fox, J. G., Elinav, E., Kucukural, A., Kumar, P., McAleer, J., Thaiss, C. A., Regev, A., Orkin, S. H., Yilmaz, O. H.. 2020-09-08. Dietary suppression of MHC-II expression in intestinal stem cells enhances intestinal tumorigenesis. https://doi.org/10.1101/2020.09.05.284174

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