TY - JOUR
T1 - Host STING-dependent MDSC mobilization drives extrinsic radiation resistance
AU - Liang, Hua
AU - Deng, Liufu
AU - Hou, Yuzhu
AU - Meng, Xiangjiao
AU - Huang, Xiaona
AU - Rao, Enyu
AU - Zheng, Wenxin
AU - Mauceri, Helena
AU - Mack, Matthias
AU - Xu, Meng
AU - Fu, Yang Xin
AU - Weichselbaum, Ralph R.
N1 - Funding Information:
The authors would like to thank Amy K. Huser for editing assistance and Rolando Torres for assistance in animal studies. This research was supported in part by Mr. & Mrs. Vincent Foglia, The Chicago Tumor Institute, The Cancer Research Foundation, an endowment from the Ludwig Cancer Research Foundation and NIH grant NCI-R21 CA195075 to R.R.W; Science and Technology Commission of Shanghai Municipality (grant 16JC1406000) and National Thousand Youth Talents Program to L.D.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-01566-5
DO - 10.1038/s41467-017-01566-5
M3 - Article
C2 - 29170400
AN - SCOPUS:85034849536
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1736
ER -