Live Biotherapeutic Lactococcus lactis GEN3013 Enhances Antitumor Efficacy of Cancer Treatment via Modulation of Cancer Progression and Immune System

SIMPLE SUMMARY: Recent studies, which have revealed the strong relationship between gut microbiota and tumor progression, have driven the clinical application of microbiome-based treatments to increase the efficacy of anticancer therapies. In particular, the genome-editing Lactococcus lactis, which activates the host immune system by expressing immune-boosting cytokines or metabolites, is a candidate for microbiome treatment. While Lactococcus lactis has so far been studied in terms of its recombinant forms, we investigated the anticancer effects of the strain-specific Lactococcus lactis GEN3013 itself. In vitro cytotoxicity tests showed that L. lactis GEN3013 inhibited the cell growth of various human and murine cancer cell lines. Consistent with the in vitro results, L. lactis GEN3013 showed antitumor effects and enhanced the therapeutic efficacy of both chemotherapy and immunotherapy in syngeneic mice. In addition, the host immune system was activated both locally and systemically by the combinatorial treatment of L. lactis GEN3013 with chemotherapy and immunotherapy. For these reasons, we suggest that L. lactis GEN3013 could be utilized as a novel biotherapeutic agent for cancer treatment. ABSTRACT: The gut microbiota is responsible for differential anticancer drug efficacies by modulating the host immune system and the tumor microenvironment. Interestingly, this differential effect is highly strain-specific. For example, certain strains can directly suppress tumor growth and enhance antitumor immunity; however, others do not have such an effect or even promote tumor growth. Identifying effective strains that possess antitumor effects is key for developing live biotherapeutic anticancer products. Here, we found that Lactococcus lactis GEN3013 inhibits tumor growth by regulating tumor angiogenesis and directly inducing cancer cell death. Moreover, L. lactis GEN3013 enhanced the therapeutic effects of oxaliplatin and the PD-1 blockade. Comprehensive immune profiling showed that L. lactis GEN3013 augmented cytotoxic immune cell populations, such as CD4(+) T cells, CD8(+) effector T cells, and NK cells in the tumor microenvironment. Our results indicate that L. lactis GEN3013 is a promising candidate for potentiating cancer treatment in combination with current standard therapy.