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

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.

• Authors: Liufu Deng, Hua Liang, Meng Xu, Xuanming Yang, Byron Burnette, Ainhoa Arina, Xiao-Dong Li, Helena Mauceri, Michael Beckett, Thomas Darga, Xiaona Huang, Thomas F Gajewski, Zhijian J Chen, Yang-Xin Fu, Ralph R Weichselbaum
• Journal: Immunity (Immunity) Vol. 41 Issue 5 Pg. 843-52 (Nov 20 2014) ISSN: 1097-4180 [Electronic] United States
• PMID: 25517616 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Vesicular Transport
• Antineoplastic Agents
• Ifnar1 protein, mouse
• Membrane Proteins
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Nucleotides, Cyclic
• RNA, Small Interfering
• Sting1 protein, mouse
• TICAM-1 protein, mouse
• Xanthones
• cyclic guanosine monophosphate-adenosine monophosphate
• vadimezan
• Receptor, Interferon alpha-beta
• Interferon-beta
• DNA
• Nucleotidyltransferases
• cGAS protein, mouse

Topics

• 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, immunology, pharmacology)
• Membrane Proteins (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Differentiation Factor 88 (genetics)
• Neoplasms (immunology, radiotherapy)
• Nucleotides, Cyclic (pharmacology)
• Nucleotidyltransferases (immunology)
• RNA Interference
• RNA, Small Interfering
• Radiation, Ionizing
• Receptor, Interferon alpha-beta (genetics, immunology)
• Signal Transduction (immunology)
• Xanthones (pharmacology)