Multi-strain, live biotherapeutics as adjuncts to checkpoint inhibitor therapy

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PROJECT SUMMARY A series of recent studies have highlighted the importance of the composition of the gut microbiota as a factor determining the efficacy of checkpoint inhibitor therapy to treat a variety of cancers. These studies have identified a number of phylogenetically unrelated taxa that lack consistency across reports, generating confusion and skepticism in the field. We evaluated the effect of prebiotics (inulin and mucin) and found that these treatments induce alterations in gut microbiota composition and lead to tumor growth attenuation in some but not all of the tumor models tested. Comparison of microbiota profiles of mice associated with effective tumor control to those that failed to do so, suggests that bacterial species encoding anti-tumor phenotypes are enriched in a number of distinct phylogenetic clades. Similarly, we observed that anti-tumor taxa are positively correlated with distinct TILs profiles suggesting that an optimized bacterial cocktail capable of stimulating multiple anti-tumor immune responses may allow more robust tumor growth control. We will test whether inulin feeding restores tumor control of gnotobiotic mice colonized with fecal microbiota from patients that were non-responsive to checkpoint inhibitor therapy. We are strongly positioned to engage in translational efforts to target the isolation and validation of relevant phylogenetic groups to identify taxa promoting improved responsiveness to checkpoint inhibitors as an important step toward developing optimized probiotic formulations for use in human patients. We will explore mechanistic aspects of inulin's ability to confer anti-tumor immunity we will conduct metabolomics analyses using gnotobiotic mice colonized with defined, low-complexity communities and in vitro cultures to identify inulin- dependent metabolites that may signal the gut immune system to induce anti-tumor immunity.