STING-dependent Cytosolic DNA Sensing Promotes Radiation-induced Type I interferon-dependent Antitumor Immunity in Immunogenic Tumors

By Liufu Deng, H. Liang, M. Xu, Xuanming Yang, Byron Burnette, A. Arina, Xiao-Dong Li, Helenna Mauceri, M. Beckett, T. Darga and 5 more. Immunity, 2014

1,896 citations recorded by the source corpus.

SUMMARY Ionizing radiation-mediated tumor regression depends on type I interferon (IFN) and the adaptive immune response, but the 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-β 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-β 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 cGAMP treatment may provide a new strategy to improve radiotherapy.

Subfields: Immunology, Infectious Diseases, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/61d95e09679d1f4195785685ae9e0f05635ad979

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Tuo Li
2. S. Tait
3. Zhijian J. Chen
4. Joel S. Riley
5. A. Ablasser
6. D. Munn
7. A. Mellor
8. J. Rehwinkel

In Infectious Diseases

1. Tuo Li
2. S. Tait
3. Joel S. Riley
4. A. Ablasser
5. A. Mellor
6. D. Munn
7. Zhijian J. Chen

In Molecular Biology

1. S. Tait
2. Zhijian J. Chen
3. A. Ablasser
4. Tuo Li
5. Joel S. Riley
6. A. Mellor
7. J. Rehwinkel
8. T. Gajewski

Citations in the corpus

• Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence (2017, positive): “Genetic defects that compromise endogenous DNA metabolism or instances that trigger massive, synchronized accumulation of dead cells represent examples of this phenomenon 26 27 28, 29 30.”
• The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer (2018, background): “Consistent with these in vitro findings, in vivo studies revealed that chemotherapy (Sistigu et al., 2014) and radiation treatment (Burnette et al., 2011; Lim et al., 2012; Deng et al., 2014) induce type I IFN signaling in tumors to promote antitumor immunity.”
• Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity (2015, background): “In addition, activation of this pathway and the subsequent production of IFN-b contributes to the anti-tumor effect of radiation (Deng et al., 2014), which can be potentiated with co-administration of a natural STING agonist.”