Gut Microbiota Modulate CD8 T Cell Responses to Influence Colitis-Associated Tumorigenesis
Amy I. Yu,
Lili Zhao,
Kathryn A. Eaton,
Sharon Ho,
Jiachen Chen,
Sara Poe,
James Becker,
Allison Gonzalez,
Delaney McKinstry,
Muneer Hasso,
Jonny Mendoza-Castrejon,
Joel Whitfield,
Charles Koumpouras,
Patrick D. Schloss,
Eric C. Martens,
Grace Y. Chen
Affiliations
Amy I. Yu
Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA
Lili Zhao
Department of Biostatistics, University of Michigan, University of Michigan, Ann Arbor, MI 48109, USA
Kathryn A. Eaton
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
Sharon Ho
College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
Jiachen Chen
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Sara Poe
Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
James Becker
Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Allison Gonzalez
College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
Delaney McKinstry
College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
Muneer Hasso
College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
Jonny Mendoza-Castrejon
Postbac Research Education Program, University of Michigan, Ann Arbor, MI 48109, USA
Joel Whitfield
Cancer Center Immunology Core, University of Michigan, Ann Arbor, MI 48109, USA
Charles Koumpouras
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
Patrick D. Schloss
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
Eric C. Martens
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
Grace Y. Chen
Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Corresponding author
Summary: There is increasing evidence that gut microbiome perturbations, also known as dysbiosis, can influence colorectal cancer development. To understand the mechanisms by which the gut microbiome modulates cancer susceptibility, we examine two wild-type mouse colonies with distinct gut microbial communities that develop significantly different tumor numbers using a mouse model of inflammation-associated tumorigenesis. We demonstrate that adaptive immune cells contribute to the different tumor susceptibilities associated with the two microbial communities. Mice that develop more tumors have increased colon lamina propria CD8+ IFNγ+ T cells before tumorigenesis but reduced CD8+ IFNγ+ T cells in tumors and adjacent tissues compared with mice that develop fewer tumors. Notably, intratumoral T cells in mice that develop more tumors exhibit increased exhaustion. Thus, these studies suggest that microbial dysbiosis can contribute to colon tumor susceptibility by hyperstimulating CD8 T cells to promote chronic inflammation and early T cell exhaustion, which can reduce anti-tumor immunity. : The gut microbiome is capable of modulating intestinal inflammation and tumorigenesis. Yu et al. demonstrate that dysbiosis can lead to increased susceptibility to inflammation-associated colon tumorigenesis via the induction of pro-inflammatory CD8+ IFNγ+ T cells, which can lead to increased T cell exhaustion within the tumor microenvironment. Keywords: microbiome, colitis, colon cancer, CD8 T cells, T cell exhaustion, inflammation
