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Article Publish Status: FREE
Abstract Title:

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

Abstract Source:

Gut. 2021 Mar 8. Epub 2021 Mar 8. PMID: 33685966

Abstract Author(s):

Wei Si, Hua Liang, Jason Bugno, Qi Xu, Xingchen Ding, Kaiting Yang, Yanbin Fu, Ralph R Weichselbaum, Xin Zhao, Liangliang Wang

Article Affiliation:

Wei Si

Abstract:

OBJECTIVE: Our goals were to evaluate the antitumour efficacy ofGG (LGG) in combination with immune checkpoint blockade (ICB) immunotherapies on tumour growth and to investigate the underlying mechanisms.

DESIGN: We 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.

RESULTS: We 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 inand, that are known to increase DC activation and CD8tumour 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 CD8T 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.

CONCLUSION: Our 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.

Study Type : In Vitro Study

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