Cell
Volume 184, Issue 21, 14 October 2021, Pages 5338-5356.e21
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Article
Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment

https://doi.org/10.1016/j.cell.2021.09.019Get rights and content
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Highlights

  • Microbiota-induced type I IFN programs antitumorigenic mononuclear phagocytes (MPs)

  • Monocytes in the TME produce type I IFN in response to microbial STING agonists

  • High-fiber diet induces type I IFN, remodels MPs in the TME, and improves ICB efficacy

  • Microbiota from ICB responders induces IFN-I and shapes the MP landscape in the TME

Summary

The tumor microenvironment (TME) influences cancer progression and therapy response. Therefore, understanding what regulates the TME immune compartment is vital. Here we show that microbiota signals program mononuclear phagocytes in the TME toward immunostimulatory monocytes and dendritic cells (DCs). Single-cell RNA sequencing revealed that absence of microbiota skews the TME toward pro-tumorigenic macrophages. Mechanistically, we show that microbiota-derived stimulator of interferon genes (STING) agonists induce type I interferon (IFN-I) production by intratumoral monocytes to regulate macrophage polarization and natural killer (NK) cell-DC crosstalk. Microbiota modulation with a high-fiber diet triggered the intratumoral IFN-I-NK cell-DC axis and improved the efficacy of immune checkpoint blockade (ICB). We validated our findings in individuals with melanoma treated with ICB and showed that the predicted intratumoral IFN-I and immune compositional differences between responder and non-responder individuals can be transferred by fecal microbiota transplantation. Our study uncovers a mechanistic link between the microbiota and the innate TME that can be harnessed to improve cancer therapies.

Keywords

tumor microenvironment
microbiota
monocytes
dendritic cells
interferon
cancer immunology
macrophages
immune checkpoint blockade immunotherapy
STING
innate immunity

Data and code availability

  • Single-cell RNA-seq data have been deposited at GEO and 16S rRNA sequencing data have been deposited at SRA. Both datasets are publicly available as of the date of publication. This paper also analyzes existing, publicly available data. All accession numbers are listed in the key resources table.

  • This study does not report original code.

  • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Cited by (0)

10

These authors contributed equally

11

Lead contact