Lactobacillus rhamnosus GG re-shapes gut microbiota and triggers STING-type I IFN-dependent antitumor immunity

Abstract

Abstract Lactobacillus rhamnosus GG (LGG) is one of the most well characterized and widely used probiotics. The beneficial roles of LGG in modulating immune response and inflammatory state during cancer development have been well demonstrated. However the true therapeutic importance of its role in current radiotherapies and immunotherapies is still unclear. Using murine models of colorectal cancer and melanoma, we demonstrate that oral administration of live LGG augmented the antitumor activity of antiPD-1 immunotherapy and/or radiotherapy in either germ-free mice or specific pathogen-free mice. Whole genome shotgun metagenome sequencing analyses revealed that the combination treatment shifted the gut microbial community towards enrichment in Bacteroidetes, Actinobacteria, Proteobacteria, and Cyanobacteria. Notably, among the enriched species, Lactobacillus murinus and Bacteroides uniformis are known to increase DC activation and CD8+ T cell tumor recruitment. Immunologically, the synergistic antitumor effect of LGG and anti-PD1 relied on the increased tumor-infiltrating dendritic cells (DCs) and cytotoxic CD8+ T cells. Mechanistically, treatment with live LGG triggered cGAS/STING-dependent type I interferon (IFN) production in DCs, which resulted in enhanced cross-priming of tumor-specific CD8+ T cells. In DCs, LGG induced IFN-β production depended on cGAS/STING/TBK1/IRF7 axis, as further evidenced by the transcriptome sequencing. Overall, our results demonstrate that oral administration of LGG mediates antitumor immunity through activating DCs in a cGAS/STING-type I IFN-dependent manner. The study provides an alternative and effective strategy to advance cancer immunotherapies and radiotherapies.