Details

Autor(en) / Beteiligte

• Yamazaki, Takahiro
• Kirchmair, Alexander
• Sato, Ai
• Buqué, Aitziber
• Rybstein, Marissa
• Petroni, Giulia
• Bloy, Norma
• Finotello, Francesca
• Stafford, Lena
• Navarro Manzano, Esther
• Ayala de la Peña, Francisco
• García-Martínez, Elena
• Formenti, Silvia C
• Trajanoski, Zlatko
• Galluzzi, Lorenzo

Titel

Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy

Ist Teil von

• Nature immunology, 2020-10, Vol.21 (10), p.1160-1171

Ort / Verlag

United States

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 mammary carcinoma cells to radiation therapy 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, mitochondrial DNA depletion or mitochondrial outer membrane permeabilization blockage via BCL2 overexpression or BAX deletion. In vivo, irradiated autophagy-incompetent mammary tumors elicited robust immunity, leading to improved control of distant nonirradiated lesions via systemic type I IFN signaling. Finally, a genetic signature of autophagy had negative prognostic value in patients with breast cancer, inversely correlating with mitochondrial abundance, type I IFN signaling and effector immunity. As clinically useful autophagy inhibitors are elusive, our findings suggest that mitochondrial outer membrane permeabilization may represent a valid target for boosting radiation therapy immunogenicity in patients with breast cancer.