Tumor-intrinsic factors dictate beneficial effect of microbiota-based therapies

Abstract Gut microbiota impacts antitumor immunity and recent studies have shown that manipulating microbiota via fecal transplant can rescue immune checkpoint blockade (ICB) response in refractory melanoma patients. However, not all patients benefited from this approach. We hypothesize that tumor-intrinsic factors (e.g. neoantigen load and immune microenvironment) contribute to the microbiota effect on anticancer response. To test this, we performed preclinical microbiota manipulation studies using dietary intervention. Mice fed high-fiber diet (FD) had improved spontaneous tumor control and response to ICB. Mechanistically, FD-induced changes in microbiota composition skewed the tumor innate immune repertoire towards an antitumor profile marked by increased dendritic cell infiltration. Downstream of the innate compartment, FD reduced the proportion of intratumoral Tregs and exhausted CD8+ T cells. We further assessed the effects of FD across 8 tumor models including EL4 lymphoma, MC38 colon carcinoma, and 6 melanomas (M1–M6) that mimic the variety of human melanoma subtypes. Although FD had a beneficial effect overall, not all models responded to the same extent, and were accompanied by different changes in the tumor immune profile. FD delayed tumor initiation for EL4 and M4, reduced growth rate for M3 and M5, both delayed initiation and reduced growth rate for MC38, M2, and M6, but had no significant effects for M1. Additionally, we found that increasing tumor immunogenicity resulted in a synergistic effect with FD. Our data suggests that tumor-intrinsic factors influence the beneficial effect of microbiota on antitumor immunity. Identifying these factors will help refine the use of microbiota-based therapies in the clinic. This research was supported by the Intramural Research Program of the NIH (CCR-NCI). This research was supported by the Intramural Research Program of the NIH (CCR-NCI).