DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity
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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.
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The record
- Venue
- Nature Communications
- Topic
- interferon and immune responses
- Field
- Immunology and Microbiology
- Canadian institutions
- —
- Funders
- National Center for Advancing Translational SciencesNational Center for Research ResourcesNational Cancer InstituteNational Institutes of HealthYork UniversityChemotherapy FoundationBreast Cancer Research FoundationWeill Cornell Medical CollegeU.S. Department of Defense
- Keywords
- Abscopal effectContext (archaeology)ImmunogenicityCancer researchCD8EffectorDNA damageImmunotherapyCancer immunotherapyImmune systemBiologyCell biologyDNAImmunologyBiochemistry
- Has abstract in OpenAlex
- yes