Extracellular vesicles derived from a specific strain of commensal bacteria promote anticancer immune responses and synergize with anticancer therapies

Abstract

Abstract Commensal microbiota regulates cancer development and influences the efficacy of anticancer therapies. To develop a novel microbiota-based anticancer therapy, we screened human intestinal bacteria for their ability to induce IL-12 production in dendritic cells (DCs). A specific strain of Lactobacillusbacteria and their extracellular vesicles (EVs) induced a high level of IL-12 production without a concomitant induction of IL-10 secretion. In addition, DCs stimulated with the LactobacillusEVs promoted differentiation of Th1 and Tc1 cells in vitro. In mice, oral or intravenous administration of the LactobacillusEVs reduced tumor growth in both subcutaneous tumor cell implantation and spontaneous colon cancer models by enhancing the production of IFN-γ and cytotoxic effector molecules in tumor-infiltrating T cells. The EVs also enhanced anticancer efficacy of an anti-PD-1 antibody and oxaliplatin treatment. The tumor growth inhibition by the LactobacillusEVs was abrogated when mice were treated with IL-12-blocking antibody, confirming that the anticancer effect of the EVs depends on their ability to induce IL-12 production. By biochemical and genetic analyses, we identified that bacterial DNA within the LactobacillusEVs is the main factor inducing IL-12 production in DCs via stimulation of TLR9. Accordingly, DNA purified from EVs of the specific Lactobacillusstrain, but not of a closely related other Lactobacillusstrain, was able to stimulate IL-12 secretion. Moreover, the EVs did not show IL-12 induction and cancer suppressive function in TLR9-deficient mice. Our results suggest that a rational selection of commensal bacteria-derived EVs can be a strategy to develop a new cancer immunotherapy. Supported by grants from the National Research Foundation of Korea (2017M3A9F3047085, 2020R1A2C2011307)