The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma

Thomsen, Martin K.; Skouboe, Morten Kelder; Boularan, Cédric; Vernejoul, Fabienne; Lioux, Thierry; Leknes, Siv L; Berthelsen, Martin F.; Riedel, Maria; Cai, Huiqiang; Joseph, Justin V.; Pérouzel, Éric; Tiraby, Michele; Vendelbo, Mikkel Holm; Paludan, Søren R.

doi:10.1038/s41388-019-1108-8

Cited by 61 publications

(57 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, previous studies revealed that STING activation can stimulate antitumor immune responses in leukemia, melanoma, glioma and hepatocellular carcinoma [91][92][93][94]. Additionally, STING expression is downregulated in a wide variety of tumor tissues and cell lines, according to a pan-cancer analysis, with a small proportion of tumors (approximately 1-25%) bearing silent STING expression [95].…”

Section: Tumor Cell Cytosolic Dsdna Induces Sting Activationmentioning

confidence: 99%

Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy

et al. 2020

View full text Add to dashboard Cite

Cellular recognition of microbial DNA is an evolutionarily conserved mechanism by which the innate immune system detects pathogens. Cyclic GMP-AMP synthase (cGAS) and its downstream effector, stimulator of interferon genes (STING), are involved in mediating fundamental innate antimicrobial immunity by promoting the release of type I interferons (IFNs) and other inflammatory cytokines. Accumulating evidence suggests that the activation of the cGAS-STING axis is critical for antitumor immunity. The downstream cytokines regulated by cGAS-STING, especially type I IFNs, serve as bridges connecting innate immunity with adaptive immunity. Accordingly, a growing number of studies have focused on the synthesis and screening of STING pathway agonists. However, chronic STING activation may lead to a protumor phenotype in certain malignancies. Hence, the cGAS-STING signaling pathway must be orchestrated properly when STING agonists are used alone or in combination. In this review, we discuss the dichotomous roles of the cGAS-STING pathway in tumor development and the latest advances in the use of STING agonists.

show abstract

Section: Tumor Cell Cytosolic Dsdna Induces Sting Activationmentioning

confidence: 99%

Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Cancer immunotherapy is an effective treatment against a number of cancers. Thomsen suggested that modulation of the cGAS-STING pathway could affect the tumor progression of HCC, and potentially be used as a treatment in patients with HCC [ 18 ]. Through overexpression and RNA interference, Wang et al demonstrated that cGAS responded to exogenous dsDNA from the DNA damage response, and subsequently triggered the activation of STING/TBK1-mediated innate immunity in chicken liver cancer [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of prognostic biomarkers and correlations with immune infiltrates among cGAS-STING in hepatocellular carcinoma

Fang

Chen

et al. 2020

Bioscience Reports

View full text Add to dashboard Cite

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway induces innate immunity by activating the production of inflammatory cytokines and type I interferons. Recently, studies revealed that self-DNA from by-products of chromosome instability and tumors could activate the cGAS-STING pathway, and subsequently promote or inhibit tumor development. However, the prognostic value and correlations with immune infiltrates of the cGAS-STING pathway in hepatocellular carcinoma (HCC) have not been clarified. In this study, we used the Molecular Signatures Database, Oncomine, UALCAN, Human Protein Atlas, Kaplan–Meier plotter, LinkedOmics, and Tumor Immune Estimation Resource databases. Overexpression of XRCC5, IRF3, TRIM21, STAT6, DDX41, TBK1, XRCC6, TREX1, PRKDC, and TMEM173 was markedly correlated with clinical stages and pathological grades in HCC. Moreover, higher mRNA expression of XRCC5, XRCC6, and PRKDC was significantly related with shorter overall survival. However, higher mRNA expression of IFI16, STAT6, NLRC3, and TMEM173 was associated with favorable overall survival. Our results suggested that the kinase targets of the cGAS-STING pathway included the SRC family of tyrosine kinases (LCK and LYN), phosphoinositide 3-kinase-related protein kinase (PIKK) family kinases (ATM and ATR), and mitogen-activated protein kinase 1 (MAPK1). Furthermore, we identified significant correlations among the expression of cGAS-STING pathway and infiltration of B cells, CD4+T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells in HCC. The expression of the cGAS-STING pathway also exhibited strong relationships with diverse immune marker sets in HCC. These findings suggest that cGAS-STING pathway members may be used as prognostic biomarkers and immunotherapeutic targets HCC patients.

show abstract

“…The importance of cGAS-STING signalling in cancer is supported by preclinical models of tumours with lost or reduced STING expression [ 46 , 51 , 52 ]. For example, loss of cGAS-STING signalling in hepatocellular carcinoma resulted in enhanced tumorigenicity and decreased CTL infiltration in non-small-cell lung carcinoma (NSCLC) [ 46 , 52 ]. However, cGAS-knockout mice were not prone to spontaneous tumour development, supporting the fact that various tumour-suppressing pathways are able to prevent tumorigenesis [ 41 ].…”

Section: Cgas-sting and Cancer Immunitymentioning

confidence: 99%

Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

Aval

Pease

Sharma

et al. 2020

JCM

145

130

View full text Add to dashboard Cite

Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a ‘cold’ tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons. Recognition of these positive immune-modulatory properties has rapidly elevated the STING pathway as a putative target for immunotherapy, leading to a myriad of preclinical and clinical studies assessing natural and synthetic cyclic dinucleotides and non-nucleotidyl STING agonists. Despite pre-clinical evidence of efficacy, clinical translation has resulted into disappointingly modest efficacy. Poor pharmacokinetic and physiochemical properties of cyclic dinucleotides are key barriers to the development of STING agonists, most of which require intra-tumoral dosing. Development of systemically administered non-nucleotidyl STING agonists, or conjugation with liposomes, polymers and hydrogels may overcome pharmacokinetic limitations and improve drug delivery. In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the numerous obstacles encountered to date, the clinical development of STING agonist as novel anti-cancer therapeutics may still hold the promise of broadening the reach of cancer immunotherapy.

show abstract

The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma

Cited by 61 publications

References 44 publications

Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy

Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy

Identification of prognostic biomarkers and correlations with immune infiltrates among cGAS-STING in hepatocellular carcinoma

Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

Contact Info

Product

Resources

About