Abstract SY39-03: Radiation-mediated DNA sensing pathway for immunity and tumor regression

Abstract

Abstract It is thought that ablative radiotherapy (RT), used for rapid control tumor growth, induces genotoxic stress and mitosis crisis leading to prolonged dormancy of irradiated tumor at local and distal site in most patients. We have unexpectedly observed that initial reduction of tumor burden following ablative RT also depends largely on type I IFN for CTL. Targeting tumor with IFN can control tumor growth through initiating a coordinated innate and adaptive immune attack against tumor cells. However, the mechanism for radiation-mediated type I IFN induction remains unclear. Here, we demonstrated that STING, but not MYD88, was required for type I IFN-dependent antitumor effects of radiation. STING in dendritic cells (DCs) controlled radiation-mediated IFN-β induction and was activated by irradiated-tumor cells. The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) mediated DCs sensing of irradiated-tumor cells. Moreover, STING was essential for radiation-induced adaptive immune responses, which relied on type I IFN signaling on DCs. Exogenous IFN-β treatment rescued cGAS/STING-deficient immune responses. Accordingly, enhancing STING signaling by cGAMP administration promoted antitumor efficacy of radiation. Our results reveal that the molecular mechanism of radiation-mediated antitumor immunity depends on a proper cytosolic DNA-sensing pathway, pointing towards a new understanding of radiation and host interactions. Furthermore, we uncover a new strategy to improve radiotherapy by cGAMP treatment. RT induced IFN can also upregulate PD-L1 that suppress T cell-mediated damage and develop radiation resistance for relapse over time. Anti-PDL-1 antibody can greatly reduce radiation resistance leading to complete tumor regression. Furthermore, our study challenges the rationale for current radio/chemotherapy strategies and highlights the importance of immune activation in preventing tumor relapse. Citation Format: Yang-xin Fu. Radiation-mediated DNA sensing pathway for immunity and tumor regression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY39-03. doi:10.1158/1538-7445.AM2015-SY39-03