Determining how the human gut microbiota modulates colon cancer tumorigenesis

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ABSTRACT Colorectal cancer (CRC) is the third most common cancer worldwide with nearly 1.4 million new cases every year, and rates are predicted to double. Emerging clinical, epidemiological and laboratory research has demonstrated an important role for gut bacteria in CRC development; however, research in this field is lacking and only a few members of the human gut microbiota have been investigated. In addition to exacerbating CRC development, microbes impact the development of effector T cell subsets that influence tumor killing. Colon tumors are often infiltrated by immune cells and disease outcome is influenced by which immune cells are recruited to tumors and their roles within the tumor microenvironment. Despite advances in other cancer types, targeted immunotherapies for colon cancer treatment have been largely unsuccessful. The microbiota could be a major factor in causing CRC and in unsuccessful immunotherapies. Therefore, I hypothesize that differences between the gut microbiotas in healthy and CRC patients contribute to CRC development and severity. To test this hypothesis, I will initially determine if the gut microbiota from human CRC patients has an effect on tumorigenesis in mouse models of CRC by colonizing Germ Free mice with the fecal microbiotas from CRC patients and matched healthy controls, and inducing CRC using an established pre-clinical mouse model for CRC. This aim will identify bacteria that modulate CRC by either exacerbation of tumorigenesis or protection from CRC. I further aim to characterize tumor infiltrating lymphocytes (TILs) within the tumor microenvironment during CRC models, and test the potential of immunogenic bacteria to increase targeted anti-tumor activity, or mitigate tolerogenic responses that hinder anti-tumor cytotoxicity, using both known and undiscovered human-derived bacteria isolated from this study. These experiments will identify novel mechanisms by which bacteria interact with TILs during CRC, and could lead to innovative immunotherapies for CRC. Lastly, I will test the hypothesis that secretory IgA sculpting, or the selection of commensal bacteria by IgA recognition, can lead to detrimental consequences by selecting for pro-tumorigenic bacteria in the colonic mucosa. These experiments will test if IgA sculpting is a mechanism by which pro-tumorigenic bacteria colonize the host. Together, results from this study will identify previously unknown bacteria as important during CRC, leading to new biomarkers and diagnostics, illuminating new strategies for immunotherapy, and gaining novel insight on the dynamic interplay between host and microbe.