Mitochondrial DNA Drives Abscopal Responses to Radiation that are Inhibited by Autophagy

Abstract

Autophagy supports both cellular and organismal homeostasis. However, whether autophagy should be inhibited or activated for cancer therapy remains unclear. Deletion of essential autophagy genes increased the sensitivity of mouse breast carcinoma cells to radiation therapy (RT), both in vitro and in vivo (in immunocompetent syngeneic hosts). Autophagy-deficient cells secreted increased amounts of type I interferon (IFN), which could be limited by CGAS or STING knockdown, and by mitochondrial DNA (mtDNA) depletion. In vivo, irradiated autophagy-incompetent breast tumors elicited robust systemic immunity leading to improved control of distant non-irradiated lesions, which could be abolished by systemic blockage of type I IFN receptors. A genetic signature of autophagy had negative prognostic value in breast cancer patients, inversely correlating with mitochondrial abundance, type I IFN signaling and effector immunity. Finally, mtDNA levels in breast tumors were positively associated with patient survival. mtDNA drives abscopal responses to RT that are inhibited by autophagy.