The University of Chicago/ Weichselbaum RR*
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.
Liang H1, Deng L2, Hou Y1, Meng X1,3, Huang X1, Rao E1, Zheng W1, Mauceri H1, Mack M4, Xu M1, Fu YX5, Weichselbaum RR6.
Ludwig Center for Metastasis Research, Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, 60637, USA.
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, Chongqing Road, Shanghai, 200025, China.
Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academic of Medical Science, 440 Jiyan Road, Jinan, 250117, China.
Department of Internal Medicine, University of Regensburg, Universitätsstrabe 31, Regensburg, 93053, Germany.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Yangxin.email@example.com.
Ludwig Center for Metastasis Research, Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, 60637, USA. firstname.lastname@example.org.