STING Signaling in Cancer Cells: Important or Not?

Arch. Immunol. Ther. Exp. DOI 10.1007/s00005-017-0481-7 REVIEW STING Signaling in Cancer Cells: Important or Not? Olga Sokolowska1,2,3 • Dominika Nowis1,4,5 Received: 30 January 2017 / Accepted: 8 July 2017 Ó The Author(s) 2017. This article is an open access publication Abstract Stimulator of interferon genes (STING) is an adaptor protein that plays an important role in the activation of type I interferons in response to cytosolic nucleic acid ligands. Recent evidence indicates involvement of the STING pathway in the induction of antitumor immune response. Therefore, STING agonists are now being extensively developed as a new class of cancer therapeutics. However, little is known about the consequences of activated STING-mediated signaling in cancer cells on the efficacy of the antitumor treatment. It has been shown that activation of the STING-dependent pathway in cancer cells can result in tumor infiltration with immune cells and modulation of the anticancer immune response. Understanding the function of STING pathway in cancer cells might provide important insights into the development of effective therapeutic strategies. This review focuses on the role of STING pathway in cancer cells, the largely unknown topic that has recently emerged to be important in the context of STING-mediated antitumor responses. & Olga Sokolowska 1 Laboratory of Experimental Medicine, Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland 2 Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland 3 Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland 4 Genomic Medicine, Medical University of Warsaw, Warsaw, Poland 5 Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland Keywords STING  Type I interferons  Innate immunity  Cancer immunology  Cyclic dinucleotides Introduction Innate immunity is a critical component of host defense against various pathogens, such as viruses, bacteria, fungi and parasites. Its functioning is based on the recognition of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) through a set of pattern recognition receptors that stimulate the downstream signaling cascades leading to production of proinflammatory mediators and type I interferons (IFNs) (Takeuchi and Akira 2010). Exogenous DNA derived from pathogens or self-DNA in the cytosol are powerful PAMPs/ DAMPs for which host organism possesses the DNA sensing systems with many DNA sensors and downstream adaptors to induce innate immune responses (Paludan and Bowie 2013). Within this system stimulator of interferon genes (STING) protein was shown to be a critical mediator of the signaling triggered by cytosolic nucleic acid derived from DNA viruses and bacteria (Ishikawa and Barber 2008; Ishikawa et al. 2009). The ability of STING to induce the production of type I IFNs drove scientists to explore this pathway in the context of antitumor immune response (Woo et al. 2014; Zhu et al. 2014). Recently, STING has emerged to be a potent target of anticancer therapies (Chandra et al. 2014; Deng et al. 2014; Ohkuri et al. 2014). It was immediately suggested that the majority of the antitumor effects caused by STING activation depend upon production of IFN-b by antigen-presenting cells (APCs) that promotes CD8? T cell priming against tumor-associated antigens (Klarquist et al. 2014; Woo et al. 2014). However, STING protein is expressed broadly in a variety 123 Arch. Immunol. Ther. Exp. of cell types including cancer cells, in which the function of the pathway has not been well characterized. STING Pathway STING (also known as MITA, MPYS, ERIS and TMEM173) is an ubiquitously expressed adaptor protein localized predominantly on the endoplasmic reticulum (ER) membrane, where it is anchored through several transmembrane domains residing in its N-terminal region (Ishikawa and Barber 2008). It is encoded by TMEM173 gene, which in humans can have up to five variants including the wild-type allele, the reference allele (R232H), the HAQ allele (R71H, G230A, R293Q), the AQ allele (G230A, R293Q), and the Q allele (R293Q), that differ in the ability to induce downstream signaling (Yi et al. 2013). In addition, the transcript can undergo the alternative splicing that results in generation of isoform lacking C-terminal domains, acting as a dominant negative regulator of STING-mediated induction of type I IFN response (Chen et al. 2014). The model of STING activation is controversial. Some studies suggest that without stimulation STING exists as a monomer that is activated by dimerization when stimulated (Sun et al. 2009; Tsuchida et al. 2010). Other studies suggest that STING forms dimers in the absence of stimulation (Ouyang et al. 2012; Shu et al. 2012). Yin et al. (2012) proposed an alternative model of activation where STING forms a dimer; however, it is inactive without stimulation due to an inhibitory interaction between the carboxyl terminal tail and the carboxyl binding domain. This interaction is disrupted upon stimulation enabling the interaction with the downstream effectors (Yin et al. 2012). STING can be activated upon detection of DNA in cytosol by different DNA sensors such as DNA-dependent activator of interferon regulatory factors (DAI), IFN-c-inducible protein 16 (IFI16), DEAD box polypeptide 41 (DDX41) (Wu and Chen 2014). However, the most critical receptor for this pathway is cyclic GMP-AMP (cGAMP) synthase (cGAS) that produces cyclic dinucleotides referred to as 20 30 cGAMP, which can bind STING directly (Ablasser et al. 2013; Civril et al. 2013; Sun et al. 2013). Activated STING translocates from the ER through the Golgi apparatus to the perinuclear microsomal compartments in a mechanism dependent on autophagy-related protein Atg9a (Ishikawa et al. 2009; Saitoh et al. 2009). Its translocation to the Golgi is required for the correct function of the STING pathway since the disruption of this process with brefeldin A treatment or expression of Shigella effector IpaJ leads to the abrogation of the downstream signaling (Ishikawa et al. 2009; Mukai et al. 2016). When STING reaches the Golgi, it forms aggregates driving activation of tank-binding 123 kinase 1 (TBK1) that subsequently phosphorylates STING. This post-translational STING modification results in the recruitment of the interferon regulatory factor 3 (IRF3) to the complex and its phosphorylation by TBK1 (Liu et al. 2015a; Tanaka and Chen 2012). After phosphorylation IRF3 translocates to the nucleus and triggers transcription of IFNB1 and several other genes, which promote expression of proinflammatory cytokines, such as interleukin 6 and tumor necrosis factor a (Ishikawa et al. 2009; Woo et al. 2014). TBK1 also activates the NF-jB pathway by phosphorylation of IKKab (Abe and Barber 2014) (Fig. 1). Post-translational Regulation of the STI (...truncated)