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STING signaling remodels the tumor microenvironment by antagonizing myeloid-derived suppressor cell expansion

Abstract

Stimulator of interferon genes (STING), a major adaptor protein in antiviral innate immune signaling, is considered as one of the most important regulators of antiviral and antitumor immunity. Although STING agonists are now intensively studied in clinical trials as a new class of adjuvants to boost cancer immunotherapy, the tumor-intrinsic role of the STING pathway in shaping the tumor microenvironment remains controversial. Here, we discovered that STING plays a vital role in regulation of myeloid-derived suppressor cell (MDSC) differentiation and antitumor immunity in Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC). Mechanistic analyses reveal that STING represses NPC-derived MDSC induction by enhancing SOCS1 expression in both tumor cells and MDSCs. SOCS1 physically interacts with STAT3 through its SH2 domain to prevent STAT3 phosphorylation and dimerization, resulting in reduced MDSC induction via inhibition of GM-CSF and IL-6 production. Notably, reduced tumoral STING expression was found to be significantly associated with a poor prognosis for NPC patients. Our findings reveal a novel mechanism linking STING to tumor microenvironmental cytokine production and MDSC induction.

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Acknowledgements

We thank Professor Hui Zhang and Jie Zhou (Zhongshan Medical School, Sun Yat-sen University) for the STING knockout mice and technical support, respectively. This work was supported by the National Natural Science Foundation of China (grant nos. 31870862, 81773256, 81572982, 81372442, and 81172164), the National Key Basic Research Program of China (2014CB910800, 2015CB859800, and 2013CB910301), the Sci-Tech Key Program of the Guangdong Province Science Foundation (grant no. 2014A020212066), and Science and Technology Planning Project of Guangzhou, China (201804010385 and 201605030012).

Author information

J.C., J.L. and Y.-X.Z. proposed the concept and conceived the entire study. C.-x.Z., S.-b.Y., J.-j.N., T.-t.C., Y.-n.L. and D.-j.H. performed experiments. H.-q.M., Q.-y.C., J.H. and X.-s.Z. selected patients and collected clinical samples. J.C., J.L. and C.-x.Z. wrote the manuscript. Y.-x.Z. helped edit the manuscript. J.C. and J.L. supervised the entire project.

Conflict of interest

The authors declare that they have no conflict of interest.

Correspondence to Yi-xin Zeng or Jiang Li or Jun Cui.

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