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. Epub 2014 Nov 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Adaptor Proteins, Vesicular Transport / genetics
  • Animals
  • Antineoplastic Agents / pharmacology
  • Cells, Cultured
  • Cross-Priming / immunology
  • DNA / immunology*
  • Dendritic Cells / immunology
  • Immunity, Innate
  • Interferon-beta / biosynthesis
  • Interferon-beta / immunology
  • Interferon-beta / pharmacology
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / genetics
  • Neoplasms / immunology
  • Neoplasms / radiotherapy*
  • Nucleotides, Cyclic / pharmacology
  • Nucleotidyltransferases / immunology*
  • RNA Interference
  • RNA, Small Interfering
  • Radiation, Ionizing
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / immunology
  • Signal Transduction / immunology
  • Xanthones / pharmacology

Substances

  • Adaptor Proteins, Vesicular Transport
  • Antineoplastic Agents
  • Ifnar1 protein, mouse
  • MPYS protein, mouse
  • Membrane Proteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Nucleotides, Cyclic
  • RNA, Small Interfering
  • TICAM-1 protein, mouse
  • Xanthones
  • cyclic guanosine monophosphate-adenosine monophosphate
  • vadimezan
  • Receptor, Interferon alpha-beta
  • Interferon-beta
  • DNA
  • Nucleotidyltransferases
  • cGAS protein, mouse