A capsular polysaccharide from a member of the healthy human microbiota activates NK cells to restrain colon cancer and aument immunotherapy 4789

Description Colorectal cancer (CRC) is the third leading cause of death in the US and is increasing globally. The microbiota is a driver of CRC pathogenesis, however, there are few microbes that are known to restrain CRC. Using transplantation of the microbiota from patients with or without CRC into germfree mice, we found that the microbiota harbored by non-diseased individuals reduced tumor formation, and we identified Bacteriodes uniformis as protective. Proactive treatment with B. uniformis slowed tumor growth in mice and increased tumor infiltrating T and Natural Killer (NK) cells, by single cell sequencing and flow cytometry. Surprisingly, NK cells, but not T-cells, were required for B. uniformis-mediated protection and B. uniformis directly upregulated NK effectors. CRC is recalcitrant to immunotherapies for unknown reasons; however, we also show that animals colonized with CRC microbiotas failed to respond to a-CTLA-4 treatment, and addition of B. uniformis restores this response, which is dependent on NK cells. We further identified that a specific B. uniformis polysaccharide capsule molecule was essential for the tumor protection and NK activation, thus identifying the relevant immunomodulatory molecule. Taken together, we have determined that healthy individuals possess tumor suppressor microbes that prevent cancer by enhancing NK immunosurveillance and anti-tumor immunity via their capsule molecules. Funding Sources This work was supported by National Institutes of Health Grants (F32CA243501) to A.M.W. University of Utah III Initiative Seed grant to JLR and NU. R01DK124336, R01DK124317 and R01AT011423, grants from the Helmsley Foundation, Burrough’s Wellcome Foundation, and the Keck Foundation to J.L.R. also supported this work.