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

Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, et al.

Immunity 2014, 41(5): 843-852.

Speaker: Li-Chun Wang (王立君)                                        Time: 15:00~16:00, Oct 21, 2015

Commentator: Dr. Bei-Chang Yang (楊倍昌老師)      Place: Room 601

Abstract:

Immunotherapy is revolutionizing the treatment of cancer patients, but the molecular basis for tumor immunogenicity is unclear. Radiotherapy is employed to treat the primary and metastatic tumors in approximately 50%–60% of all cancer patients.¹ Radiotherapy has been shown to sculpt innate immune response in a type I interferon (IFN)-dependent manner to facilitate adaptive immune response.² However, the molecular mechanism for host type I IFN induction following radiation has not yet been defined. Moreover, several pathways control type I IFN. Recently, endoplasmic-reticulum-associated protein STING has been demonstrated to be a mediator for type I IFN induction by intracellular exogenous DNA in a TLR-independent manner. Here, authors demonstrate that adaptor protein STING is required for type I IFN-dependent antitumor effects of radiation but not MyD88 and TRIF. Activation of STING-IRF3 by irradiated-tumor cells controls type I IFN induction in dendritic cells (DCs) and that this process is crucial for the ability of DCs to cross-prime CD8⁺ T cells. In addition, the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) is essential for DCs mediated sensing of irradiated-tumor cells. Besides, type I IFN signaling on DCs is required for antitumor efficacy of radiation by boosting adaptive immune responses. Finally, exogenous cyclic GMP-AMP (cGAMP) treatment synergizes with radiation to control tumors in a STING-dependent manner. Taken together, they reveal a molecular mechanism of radiation-mediated antitumor immunity and highlight the potential to improve radiotherapy by cGAMP administration.

References：

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2.         Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR, et al. The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer research 2011, 71(7): 2488-2496.