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Immunity. 2014 Nov 20;41(5):843-52. doi: 10.1016/j.immuni.2014.10.019. Epub 2014 Nov 6.

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

Author information

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: yfu@uchicago.edu.
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: rrw@radonc.uchicago.edu.

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.

PMID:
25517616
PMCID:
PMC5155593
DOI:
10.1016/j.immuni.2014.10.019
[Indexed for MEDLINE]
Free PMC Article

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