Low, repeated radiation doses result in a buildup of double-stranded DNA (dsDNA) which activates, in turn, the cGAS/STING pathway, production of IFNβ, and recruitment of dendritic cells and CD8+ T cells. Higher radiation doses induce the regulatory DNAse Trex1, which degrades the intracellular dsDNA and halts the DNA damage-induced immunogenic process.
Radiotherapy is under investigation for its ability to enhance responses to immunotherapy. However, the mechanisms by which radiation induces anti-tumour T cells remain unclear. We show that the DNA exonuclease Trex1 is induced by radiation doses above 12-18 Gy in different cancer cells, and attenuates their immunogenicity by degrading DNA that accumulates in the cytosol upon radiation. Cytosolic DNA stimulates secretion of interferon-beta by cancer cells following activation of the DNA sensor cGAS and its downstream effector STING. Repeated irradiation at doses that do not induce Trex1 amplifies interferon-beta production, resulting in recruitment and activation of Batf3-dependent dendritic cells. This effect is essential for priming of CD8+ T cells that mediate systemic tumour rejection (abscopal effect) in the context of immune checkpoint blockade. Thus, Trex1 is an upstream regulator of radiation-driven anti-tumour immunity. Trex1 induction may guide the selection of radiation dose and fractionation in patients treated with immunotherapy.
Author Info: (1) Department of Radiation Oncology, Weill Cornell Medicine, 1300 York Avenue, Box 169, New York, New York 10065, USA. (2) Department of Microbiology, New York University School o
Author Info: (1) Department of Radiation Oncology, Weill Cornell Medicine, 1300 York Avenue, Box 169, New York, New York 10065, USA. (2) Department of Microbiology, New York University School of Medicine, 450 29th Street, New York, New York 10016, USA. Present address: Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Tumor Biology Department, Toulouse 31062, France. (3) Radiation Oncology Branch, Center for Cancer Research and Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Building #10, Room B3 B406, 9000 Rockville Pike, Bethesda, Maryland 20892, USA. (4) Department of Radiation Oncology, Weill Cornell Medicine, 1300 York Avenue, Box 169, New York, New York 10065, USA. (5) Department of Radiation Oncology, Weill Cornell Medicine, 1300 York Avenue, Box 169, New York, New York 10065, USA. (6) Department of Microbiology, New York University School of Medicine, 450 29th Street, New York, New York 10016, USA. (7) Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 525 East 68th Street, New York, New York 10065, USA. (8) Radiation Oncology Branch, Center for Cancer Research and Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Building #10, Room B3 B406, 9000 Rockville Pike, Bethesda, Maryland 20892, USA. (9) Department of Radiation Oncology, Weill Cornell Medicine, 1300 York Avenue, Box 169, New York, New York 10065, USA. (10) Department of Radiation Oncology, Weill Cornell Medicine, 1300 York Avenue, Box 169, New York, New York 10065, USA. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 525 East 68th Street, New York, New York 10065, USA.
