Host STING-dependent MDSC mobilization drives extrinsic radiation resistance

• Published in: Nature communications 2017-11, Vol.8 (1), p.1736-10, Article 1736
• Main Authors: Liang, Hua, Deng, Liufu, Hou, Yuzhu, Meng, Xiangjiao, Huang, Xiaona, Rao, Enyu, Zheng, Wenxin, Mauceri, Helena, Mack, Matthias, Xu, Meng, Fu, Yang-Xin, Weichselbaum, Ralph R.
• Format: Article
• Language: English
• Subjects: 631/250/251/1574; 631/67/327; Activation; Adaptive Immunity; Animals; Anticancer properties; CCR2 protein; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Colonic Neoplasms - immunology; Colonic Neoplasms - radiotherapy; Female; Humanities and Social Sciences; Humans; Immunity; Immunity, Innate; Immunosuppression; Infiltration; Interferon; Interferon Type I - metabolism; Membrane Proteins - immunology; Metastases; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocyte chemoattractant protein 1; Monocytes; multidisciplinary; Myeloid cells; Myeloid-Derived Suppressor Cells - immunology; Radiation; Radiation effects; Radiation therapy; Radiation tolerance; Radiation Tolerance - immunology; Radioresistance; Receptors, CCR2 - deficiency; Receptors, CCR2 - genetics; Receptors, CCR2 - immunology; Science; Science (multidisciplinary); Signal Transduction; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-01566-5

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. Tumors often develop resistance to radiotherapy. Here the authors show that irradiation leads to a CCR2-dependent infiltration by myeloid derived suppressor cells that promote radio-resistance through inhibition of adaptive immune responses and that the use of CCR2 antibodies in mice reduces such resistance.