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- Title
DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity.
- Authors
Vanpouille-Box, Claire; Alard, Amandine; Aryankalayil, Molykutty J.; Sarfraz, Yasmeen; Diamond, Julie M.; Schneider, Robert J.; Inghirami, Giorgio; Coleman, C. Norman; Formenti, Silvia C.; Demaria, Sandra
- Abstract
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-β 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-β 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.
- Publication
Nature Communications, 2017, Vol 8, Issue 6, p15618
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/ncomms15618