DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Academic Article uri icon

Overview

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 date

  • June 9, 2017

Research

keywords

  • CD8-Positive T-Lymphocytes
  • Dendritic Cells
  • Exodeoxyribonucleases
  • Mammary Neoplasms, Animal
  • Neoplasms
  • Phosphoproteins

Identity

PubMed Central ID

  • PMC5472757

Scopus Document Identifier

  • 85019727443

Digital Object Identifier (DOI)

  • 10.1038/ncomms15618

PubMed ID

  • 28598415

Additional Document Info

volume

  • 8