Dietary Lactobacillus-Derived Exopolysaccharide Enhances Immune-Checkpoint Blockade Therapy

Microbes and their byproducts have been reported to regulate host health and immune functions. Here we demonstrated that microbial exopolysaccharide produced by Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 (EPS-R1) induced CCR6(+) CD8(+) T cells of mice and humans. In mice, ingestion of EPS-R1 augmented antitumor effects of anti-CTLA-4 or anti-PD-1 monoclonal antibody against CCL20-expressing tumors, in which infiltrating CCR6(+) CD8(+) T cells were increased and produced IFN gamma accompanied by a substantial immune response gene expression signature maintaining T-cell functions. Of note, the antitumor adjuvant effect of EPS-R1 was also observed in germ-free mice. Furthermore, the induction of CCR6(+) expression was mediated through the phosphorylated structure in EPS-R1 and a lysophosphatidic acid receptor on CD8(+) T cells. Overall, we find that dietary EPS-R1 consumption induces CCR6(+) CD8(+) T cells in Peyer's patches, favoring a tumor microenvironment that augments the therapeutic effect of immune-checkpoint blockade depending on CCL20 production by tumors. SIGNIFICANCE: Gut microbiota- and probiotic-derived metabolites are attractive agents to augment the efficacy of immunotherapies. Here we demonstrated that dietary consumption of Lactobacillus-derived exopolysaccharide induced CCR6(+) CD8(+) T cells in Peyer's patches and improved the tumor microenvironment to augment the therapeutic effects of immune-checkpoint blockade against CCL20-producing tumors.