Host STING-dependent MDSC mobilization drives extrinsic radiation resistance

Hua Liang, Liufu Deng, Yuzhu Hou, Xiangjiao Meng, Xiaona Huang, Enyu Rao, Wenxin Zheng, Helena Mauceri, Matthias Mack, Meng Xu, Yang Xin Fu, Ralph R. Weichselbaum

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57 Scopus citations

Abstract

Radiotherapy induces and promotes innate and adaptive immunity in which host STING plays an important role. However, radioresistance in irradiated tumors can also develop, resulting in relapse. Here we report a mechanism by which extrinsic resistance develops after local ablative radiation that relies on the immunosuppressive action of STING. The STING/type I interferon pathway enhances suppressive inflammation in tumors by recruiting myeloid cells in part via the CCR2 pathway. Germ-line knockouts of CCR2 or treatment with an anti-CCR2 antibody results in blockade of radiation-induced MDSC infiltration. Treatment with anti-CCR2 antibody alleviates immunosuppression following activation of the STING pathway, enhancing the anti-tumor effects of STING agonists and radiotherapy. We propose that radiation-induced STING activation is immunosuppressive due to (monocytic) M-MDSC infiltration, which results in tumor radioresistance. Furthermore, the immunosuppressive effects of radiotherapy and STING agonists can be abrogated in humans by a translational strategy involving anti-CCR2 antibody treatment to improve radiotherapy.

Original languageEnglish (US)
Article number1736
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Liang, H., Deng, L., Hou, Y., Meng, X., Huang, X., Rao, E., Zheng, W., Mauceri, H., Mack, M., Xu, M., Fu, Y. X., & Weichselbaum, R. R. (2017). Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nature Communications, 8(1), [1736]. https://doi.org/10.1038/s41467-017-01566-5