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Host STING-dependent MDSC mobilization drives extrinsic radiation resistance.


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.

SUBMITTER: Liang H 

PROVIDER: S-EPMC5701019 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Host STING-dependent MDSC mobilization drives extrinsic radiation resistance.

Liang Hua H   Deng Liufu L   Hou Yuzhu Y   Meng Xiangjiao X   Huang Xiaona X   Rao Enyu E   Zheng Wenxin W   Mauceri Helena H   Mack Matthias M   Xu Meng M   Fu Yang-Xin YX   Weichselbaum Ralph R RR  

Nature communications 20171123 1


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 knockou  ...[more]

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