DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28598415.
- Also identified by DOI 10.1038/ncomms15618 and PMC identifier 5472757.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>+</sup> 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.
Medical subject headings
- CD8-Positive T-Lymphocytes
- Dendritic Cells
- Exodeoxyribonucleases
- Mammary Neoplasms, Animal
- Neoplasms
- Phosphoproteins