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Host STING-dependent MDSC mobilization drives extrinsic radiation resistance

Author

Listed:
  • Hua Liang

    (Ludwig Center for Metastasis Research, Department of Radiation and Cellular Oncology, The University of Chicago)

  • Liufu Deng

    (Shanghai Institute of Immunology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, 280 South)

  • Yuzhu Hou

    (Ludwig Center for Metastasis Research, Department of Radiation and Cellular Oncology, The University of Chicago)

  • Xiangjiao Meng

    (Ludwig Center for Metastasis Research, Department of Radiation and Cellular Oncology, The University of Chicago
    Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academic of Medical Science)

  • Xiaona Huang

    (Ludwig Center for Metastasis Research, Department of Radiation and Cellular Oncology, The University of Chicago)

  • Enyu Rao

    (Ludwig Center for Metastasis Research, Department of Radiation and Cellular Oncology, The University of Chicago)

  • Wenxin Zheng

    (Ludwig Center for Metastasis Research, Department of Radiation and Cellular Oncology, The University of Chicago)

  • Helena Mauceri

    (Ludwig Center for Metastasis Research, Department of Radiation and Cellular Oncology, The University of Chicago)

  • Matthias Mack

    (University of Regensburg)

  • Meng Xu

    (Ludwig Center for Metastasis Research, Department of Radiation and Cellular Oncology, The University of Chicago)

  • Yang-Xin Fu

    (University of Texas Southwestern Medical Center)

  • Ralph R. Weichselbaum

    (Ludwig Center for Metastasis Research, Department of Radiation and Cellular Oncology, The University of Chicago)

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.

Suggested Citation

  • 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, 2017. "Host STING-dependent MDSC mobilization drives extrinsic radiation resistance," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01566-5
    DOI: 10.1038/s41467-017-01566-5
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