Determining immune-mediated mechanisms of beneficial bacteria in colon cancer

About This Grant

PROJECT SUMMARY Colorectal Cancer (CRC) is a significant burden on human health and in need of better diagnostics and treatments. Microbes have been implicated in ~20% of all human cancers, and recent studies have shown strong associations of CRC with bacteria residing in the gut. The gut microbiota has well-established roles in modulating intestinal immune responses that can exacerbate or alleviate inflammation, however, the ways in which members of the gut microbiota modulate pro or anti-tumor immune responses remain largely unknown. Colonic tumors are infiltrated by surrounding immune cells and disease outcome is heavily influenced by which immune cells are recruited to tumors and their roles within the tumor microenvironment (TME), therefore, understanding the mechanisms of how gut bacteria can modulate those infiltrating immune cells is critical in designing new and more improved diagnostics and interventions. In my work investigating human microbiotas from CRC patients, I discovered a human gut commensal, Bacteroides uniformis, protects against disease by enhancing anti-tumor immunity. This protection is dependent on Natural Killer (NK) cells and is effective in multiple pre-clinical mouse tumor models. I found that B. uniformis directly activates NK cells, and this effect is independent of adaptive immunity. However, the bacterial factors recognized by NKs are still unknown, as are the dynamics within the NK cells after B. uniformis stimulation in the gut and TME. B. uniformis and other Bacteroides spp. can modulate immune responses via their unique capsule polysaccharides, but their impact on anti-tumor immunity is unknown. Therefore, I hypothesize that B. uniformis directly activates NK cells, through its capsule molecules, resulting in remodeling of the immune landscape in the tumor microenvironment, and enhancing anti- tumor immunity to protect against CRC. I will investigate this hypothesis along three lines of interrogation. Specific Aim 1: Identify the bacterial factor by which B. uniformis modulates NK cell activation and cytotoxicity. Specific Aim 2: Determine how strain level genetic variations in B. uniformis influences immune activation and CRC development. Specific Aim 3: Investigate how bacterial induced NK activation in the tumor microenvironment promotes anti-tumor immunity. By completion of this proposed work I will have a more nuanced understanding of the mechanisms by which B. uniformis prevents tumor formation via NK cells in the TME, which will lead to translational progress in innovative diagnostics and novel therapies for patients with CRC.