Intestinal microbiota modulates the anti-tumor effect of oncolytic virus vaccine in colorectal cancer

BackgroundImmunotherapy such as oncolytic virus has become a powerful cancer treatment but only a part of cancer patients can benefit from it, especially to advanced-stage cancer patients are required new therapeutic strategies to facilitate extended survival. Intestinal microbiota may contribute to colorectal cancer (CRC) carcinogenesis and response to immunotherapy. However, whether and how the modulating effect of intestinal microbiota on oncolytic virus vaccine (OVV) in CRC remains to be investigated. MethodsWe generated a MC38-gp33 CRC mouse model and treated with OVV-gp33 in early- and advanced-stages. Probiotics, fecal microbiota transplantation (FMT) and antibiotics (ABX) were treated to regulate the microbial composition of CRC mice of advanced stage. The tumor growth rate and survival time of mice were recorded. 16S rDNA sequencing analyzed the microbial composition and flow cytometry detected the T cells subsets activity. ResultsOVV-gp33 treatment led to inhibited tumor growth and prolonged survival in the early stage of CRC but did not have a significant effect on the advanced stage of CRC. Moreover, 16S rDNA sequence analysis and flow cytometry showed significant differences in intestinal microbiota composition, microbial metabolites and T-cell subsets in early- and advanced-stage CRC. Probiotic and FMT treatment significantly enhanced the antitumor effect of OVV in advanced stage of CRC with an increased abundance of activated CD8+ T cells and a decreased ratio of Treg cells, while depletion of the microbiota by ABX eliminated the antitumor activity of OVV with decreased CD8+ T-cell activation and upregulated Treg cells. ConclusionsThese results indicate that intestinal microbiota and microbial metabolites play an important role in the OVV antitumor effect in CRC, furthermore, altering the intestinal microbiota composition can modulate the antitumor and immunomodulatory effect of OVV in CRC.