Lactobacillus rhamnosus GG induces cGAS/STING- dependent type I interferon and improves response to immune checkpoint blockade

Abstract

ObjectiveOur goals were to evaluate the antitumour efficacy of Lactobacillus rhamnosus GG (LGG) in combination with immune checkpoint blockade (ICB) immunotherapies on tumour growth and to investigate the underlying mechanisms.DesignWe used murine models of colorectal cancer and melanoma to evaluate whether oral administration of LGG improves the efficacy of ICB therapies. We performed the whole genome shotgun metagenome sequencing of intestinal contents and RNA sequencing of dendritic cells (DCs). In a series of in vitro and in vivo experiments, we further defined the immunological and molecular mechanisms of LGG-mediated antitumour immunity.ResultsWe demonstrate that oral administration of live LGG augmented the antitumour activity of anti-programmed cell death 1 (PD-1) immunotherapy by increasing tumour-infiltrating DCs and T cells. Moreover, the combination treatment shifted the gut microbial community towards enrichment in Lactobacillus murinus and Bacteroides uniformis, that are known to increase DC activation and CD8+tumour recruitment. Mechanistically, treatment with live LGG alone or in combination with anti-PD-1 antibody triggered type I interferon (IFN) production in DCs, enhancing the cross-priming of antitumour CD8+ T cells. In DCs, cyclic GMP-AMP synthase (cGAS)/stimulator of IFN genes (STING) was required for IFN-β induction in response to LGG, as evidenced by the significant decrease in IFN-β levels in cGAS or STING-deficient DCs. LGG induces IFN-β production via the cGAS/STING/TANK binding kinase 1/interferon regulatory factor 7 axis in DCs.ConclusionOur findings have offered valuable insight into the molecular mechanisms of live LGG-mediated antitumour immunity and establish an empirical basis for developing oral administration of live LGG as a combination agent with ICB for cancer therapies.

Novel insights on gut microbiota manipulation and immune checkpoint inhibition in cancer (Review)

“…The role of the STING pathway in potentiating the efficacy of immunotherapy, was also proven by Shi et al ( 136 ). In agreement with the findings of Si et al ( 135 ), Shi et al ( 136 ) observed that a specific gut microbe, Bifidobacterium spp., potentiated anti-CD47 immunotherapy via the stimulation of STING in DCs in tumor-bearing mice.…”

“…More recently, in 2021, Si et al ( 135 ) evaluated the therapeutic efficacy of administering a single bacterial strain, Lactobacillus rhamnosus GG (LGG) in combination with ICI immunotherapy. Pivotally, the oral administration of LGG significantly improved the efficacy of ICIs and reduced tumor growth in CRC and melanoma mouse models.…”

“…Pivotally, the oral administration of LGG significantly improved the efficacy of ICIs and reduced tumor growth in CRC and melanoma mouse models. The authors further explored the molecular mechanism, evidencing that the augmented anti-tumor activity of anti-PD-1 was associated with increased tumor-infiltrating DCs and CD8 + T-cells ( 135 ). Moreover, treatments with live LGG alone or in combination with anti-PD-1 triggered type I IFN production by DCs, enhancing the cross-priming of CD8 + cytotoxic T-cells.…”

“…In DCs, cyclic GMP-AMP synthase (cGAS)/stimulator of IFN genes (STING) was required for IFN-β induction in response to LGG. In fact, LGG significantly boosted IFN-β production via the cGAS/STING axis in DCs ( 135 ). The role of the STING pathway in potentiating the efficacy of immunotherapy, was also proven by Shi et al ( 136 ).…”

The Cytosolic DNA-Sensing cGAS-STING Pathway in Liver Diseases

“…Treatment of mice after HCC development with 3′3′-cAIMP, a cyclic dinucleotide STING agonist, effectively reduces the tumor size in cGAS –/– mice, which cannot generate 2′3′-cGAMP ( Thomsen et al, 2020 ). In addition, Lactobacillus rhamnosus GG induces cGAS/STING-dependent IFN-β production and improves the response to anti-programmed cell death 1 (PD-1) immunotherapy ( Si et al, 2021 ). Therefore, regulation by STING pathway agonists may reverse the development of HCC and is expected to be an effective treatment strategy.…”