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

被引：1616

作者：

Deng, Liufu ^{[1
,3
]}

Liang, Hua ^{[1
,3
]}

Xu, Meng ^{[2
]}

Yang, Xuanming ^{[2
]}

Burnette, Byron ^{[1
,3
]}

Arina, Ainhoa ^{[1
,3
]}

Li, Xiao-Dong ^{[4
]}

Mauceri, Helena ^{[1
,3
]}

Beckett, Michael ^{[1
,3
]}

Darga, Thomas ^{[1
,3
]}

Huang, Xiaona ^{[1
]}

Gajewski, Thomas F. ^{[2
]}

Chen, Zhijian J. ^{[4
,5
]}

Fu, Yang-Xin ^{[2
,3
]}

Weichselbaum, Ralph R. ^{[1
,3
]}

机构：

[1] Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA

[2] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA

[3] Univ Chicago, Ludwig Ctr Metastasis Res, Chicago, IL 60637 USA

[4] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA

[5] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA

来源：

IMMUNITY | 2014年 / 41卷 / 05期

基金：

美国国家卫生研究院;

关键词：

CYCLIC GMP-AMP; INNATE; CELLS; 2ND-MESSENGER; RECOGNITION; ACTIVATION; RECEPTORS; THERAPY; ADAPTER; SYSTEM;

D O I：

10.1016/j.immuni.2014.10.019

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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-beta 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-beta 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.

引用

页码：843 / 852

页数：10