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.
Highlights
Radiotherapy induces and promotes innate and adaptive immunity in which host STING plays an important role
The potential importance of CCR2-expressing cells in radiation therapy is observed in the Lewis Lung Carcinoma (LLC) tumor model, where LLC tumors grown in CCR2−/− hosts showed significant regression post-IR compared to LLC grown in WT mice (Fig. 2b, CCR2−/− IR 228 ± 166 vs. WT IR 1300 ± 199, day 24, P < 0.01: Student’s t-test). These results suggest that CCR2+ myeloid-derived suppressor cells (MDSCs) contribute to tumor relapse after radiation therapy, and indicate that CCR2 is a therapeutic target for improvement of radiation efficacy
We reported that an extrinsic mechanism of tumor radioresistance is regulated by host CCR2+ M-MDSCs (CCR2+Ly6chi)
Summary
Radiotherapy induces and promotes innate and adaptive immunity in which host STING plays an important role. The STING/type I interferon pathway enhances suppressive inflammation in tumors by recruiting myeloid cells in part via the CCR2 pathway. Treatment with antiCCR2 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. Therapeutic radiation leads to injury-like inflammation locally that induces inflammatory responses[13] that are anti-tumor in nature and immunosuppressive. These immunosuppressive pathways include recruitment of myeloid-derived suppressor cells (MDSCs)[14] and regulatory T cells (Tregs)[15]. M-MDSCs express higher levels of F4/80, CD115, 7/4, and CCR2
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