Microbial regulation of anti-tumor immunity in colorectal cancer

Abstract Colorectal cancer (CRC) is one of the most common and deadly types of cancer. Although recent advances in early detection and revolutionary therapies such as checkpoint blockade immunotherapy resulted in improved outcomes in CRC, a large fraction of CRC patients, particularly with metastasis, do not respond well to existing immunotherapy modalities. This necessitates a better mechanistic understanding on tumor – immune cell interactions in the context of CRC. Microbiome influences multiple biological aspects of the host including immune responses against cancers. We recently defined a causal role for microbiome in regulating epithelial stem cell MHC-II expression and tumor initiation in the intestine. Here we expound on the significance of microbiome - MHC-II axis in CRC progression and metastasis. We found that colonization of microbes that correlate epithelial MHC-II expression in the intestine restricts CRC progression and improves overall survival in three different clinically-relevant orthotopic CRC models across mice strains. Notably, microbiome-induced anti-tumor effects are dependent on T cells. Finally, genetic inactivation of MHC-II in cancer cells diminished tumor preventing effects of microbes. These results underscore a causal role for microbe - MHC-II axis in regulating anti-tumor immunity during tumor progression. Microbes that boost MHC-II expression promote anti-tumor immunity in the colon, which may synergize with therapeutic approaches such as immunotherapy. NIH (P30CA045508-33 to S.B.), the Oliver S. and Jennie R. Donaldson Charitable Trust (S.B.), The Harold and Leila Y. Mathers Charitable Foundation (S.B), The Mark Foundation for Cancer Research (20-028-EDV to S.B.) and STARR Cancer Consortium (I13-0052 to S.B.), Chan Zuckerberg Initiative / Silicon Valley Community Foundation (2021-239862)