DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity

Claire Vanpouille-Box, Amandine Alard, Molykutty J. Aryankalayil, Yasmeen Sarfraz, Julie M. Diamond, Robert J. Schneider, Giorgio Inghirami, C. Norman Coleman, Silvia C. Formenti and Sandra Demaria ()
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Claire Vanpouille-Box: Weill Cornell Medicine
Amandine Alard: New York University School of Medicine
Molykutty J. Aryankalayil: Radiation Oncology Branch, Center for Cancer Research and Radiation Research Program, National Cancer Institute, NIH
Yasmeen Sarfraz: Weill Cornell Medicine
Julie M. Diamond: Weill Cornell Medicine
Robert J. Schneider: New York University School of Medicine
Giorgio Inghirami: Weill Cornell Medicine
C. Norman Coleman: Radiation Oncology Branch, Center for Cancer Research and Radiation Research Program, National Cancer Institute, NIH
Silvia C. Formenti: Weill Cornell Medicine
Sandra Demaria: Weill Cornell Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15618

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