DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity

By C. Vanpouille‐Box, A. Alard, M. Aryankalayil, Yasmeen Sarfraz, J. Diamond, R. Schneider, G. Inghirami, C. Coleman, S. Formenti, S. Demaria. Nature Communications, 2017

1,580 citations recorded by the source corpus.

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. Trex1 is an exonuclease that degrades cytosolic DNA and has been associated with modulation of interferon responses in autoimmunity and viral infections. Here, the authors show that Trex1 attenuates the immunogenicity of cancer cells treated with high radiation doses by degrading cytosolic DNA and preventing the activation of interferon response.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2c08ccce07847a7d93b57ac852adaf1491fec18e

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Citations in the corpus

Mitochondrial metabolism and cancer (2017, background): “That said, the release of mtDNA upon MOMP promotes the secretion of type I interferon (IFN) by malignant cells, and this is required for the activation of optimal anticancer immune responses upon chemotherapy and radiation therapy [202-205].”
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “Further underscoring the complexity of the interaction between inflammation and pyroptosis [649], CASP11 can also be upregulated by a complement cascade dependent on carboxypeptidase B1 (CPB1) acting downstream of TLR4 and IFNAR1 activation [650].”
Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11 (2019, background): “More recently, cGAS–STING sensing of cytoplasmic DNA and micronuclei following radiation has emerged as an important connection between innate immunity and radiotherapy (3, 4, 32).”