STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors

  • Immunity. 2014 Nov 20;41(5):843-52. doi: 10.1016/j.immuni.2014.10.019.
Liufu Deng  1 ,  Hua Liang  1 ,  Meng Xu  2 ,  Xuanming Yang  2 ,  Byron Burnette  1 ,  Ainhoa Arina  1 ,  Xiao-Dong Li  3 ,  Helena Mauceri  1 ,  Michael Beckett  1 ,  Thomas Darga  1 ,  Xiaona Huang  4 ,  Thomas F Gajewski  2 ,  Zhijian J Chen  5 ,  Yang-Xin Fu  6 ,  Ralph R Weichselbaum  7
Affiliations
  • 1. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA.
  • 2. Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
  • 3. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
  • 5. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 6. Department of Pathology, University of Chicago, Chicago, IL 60637, USA; The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA. Electronic address: [email protected].
  • 7. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA. Electronic address: [email protected].
PMID: 25517616 DOI: 10.1016/j.immuni.2014.10.019
Abstract

Ionizing radiation-mediated tumor regression depends on type I interferon (IFN) and the adaptive immune response, but several pathways control I IFN induction. Here, we demonstrate that adaptor protein STING, but not MyD88, is required for type I IFN-dependent antitumor effects of radiation. In dendritic cells (DCs), STING was required for IFN-? induction in response to irradiated-tumor cells. The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) mediated sensing of irradiated-tumor cells in DCs. Moreover, STING was essential for radiation-induced adaptive immune responses, which relied on type I IFN signaling on DCs. Exogenous IFN-? treatment rescued the cross-priming by cGAS or STING-deficient DCs. Accordingly, activation of STING by a second messenger cGAMP administration enhanced antitumor immunity induced by radiation. Thus radiation-mediated antitumor immunity in immunogenic Tumors requires a functional cytosolic DNA-sensing pathway and suggests that cGAMP treatment might provide a new strategy to improve radiotherapy.