Targeting STING pathways for the treatment of cancer

Gravekamp, Claudia; Chandra, Dinesh

doi:10.4161/2162402x.2014.988463

Cited by 18 publications

(13 citation statements)

References 11 publications

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“…Besides, other cytokines could also be regulated by STING, for example, IL-6 is responsible for the production of neutrophils, supports the growth of B cells and is antagonistic to regulatory T cells 32 . IL-12 leads to proliferation and activation of CD8 + T cells 33 , and CXCL10 may chemo-attract several kinds of immune cells 34 . Reduced STING expression rendered gastric cancer cells a defective function to produce type I interferon and other immune cytokines such as IL-6 after exposure to cytosolic DNA or its agonist cGAMP ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Decreased expression of STING predicts poor prognosis in patients with gastric cancer

Song

Peng

Tang

et al. 2017

Sci Rep

159

134

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STING (stimulator of interferon genes) has recently been found to play an important role in host defenses against virus and intracellular bacteria via the regulation of type-I IFN signaling and innate immunity. Chronic infection with Helicobacter pylori is identified as the strongest risk factor for gastric cancer. Thus, we aim to explore the function of STING signaling in the development of gastric cancer. Immunohistochemistry was used to detect STING expression in 217 gastric cancer patients who underwent surgical resection. STING protein expression was remarkably decreased in tumor tissues compared to non-tumor tissues, and low STING staining intensity was positively correlated with tumor size, tumor invasion depth, lymph mode metastasis, TNM stage, and reduced patients’ survival. Multivariate analysis identified STING as an independent prognostic factor, which could improve the predictive accuracy for overall survival when incorporated into TNM staging system. In vitro studies revealed that knock-down of STING promoted colony formation, viability, migration and invasion of gastric cancer cells, and also led to a defect in cytosolic DNA sensing. Besides, chronic H. pylori infection up-regulated STING expression and activated STING signaling in mice. In conclusion, STING was proposed as a novel independent prognostic factor and potential immunotherapeutic target for gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Decreased expression of STING predicts poor prognosis in patients with gastric cancer

Song

Peng

Tang

et al. 2017

Sci Rep

159

134

View full text Add to dashboard Cite

show abstract

“…Interfering with bacterial signaling can aid the development of novel anti-infectives, as well as the production of natural nanomaterials of biotechnological use 98,99 . The mammalian pathways, on the other hand, can be exploited in immunization approaches or the pharmacological targeting of infections and cancer 80,100 . Hopefully, future studies on the adaptational and virulence strategies of bacteria, as well as their evolutionary patterns, can be further harnessed to humankind’s advantage.…”

Section: Discussionmentioning

confidence: 99%

Versatile modes of cellular regulation via cyclic dinucleotides

2017

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Since the discovery of c-di-GMP almost three decades ago, cyclic dinucleotides (CDNs) have emerged as widely used signaling molecules in most kingdoms of life. The family of second messengers now includes c-di-AMP and distinct versions of mixed cyclic GMP-AMP (cGAMP) compounds. Along with these nucleotides, a vast number of proteins for the production and turnover of these molecules have been described, as well as effectors that translate the signals into physiological responses. The latter include but are not limited to mechanisms for adaptation and survival in prokaryotes, persistence and virulence of bacterial pathogens, as well as immune responses to viral and bacterial invasion in eukaryotes. In this review we will focus on recent discoveries and emerging themes that illustrate the ubiquity and versatility of cyclic dinucleotide function at the transcriptional and post-translational levels and, in particular, on insights gained through mechanistic structure-function analyses.

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“…112 Corroborating initial findings, the intratumoral or systemic administration of DMXAA or other STING agonists, alone or combined with other therapeutic agents, have ultimately been attributed pronounced therapeutic effects in numerous murine models of fibrosarcoma, glioma, 80 melanoma, 66,113 as well as breast, 114-117 colorectal 118 and prostate carcinoma. 119 Moreover, various CDNs have been shown to boost the therapeutic activity of anticancer vaccines in a variety of tumor models, including (1) mouse 4T1 triple-negative mammary carcinomas treated with a Listeria monocytogenes-based vaccine; [120][121][122] (2) mouse B16 melanomas treated with the TRIVAX vaccine, which consists of synthetic peptides, the Tolllike receptor 3 (TLR3) agonist polyinosinic:polycytidylic acid (polyI:C) 123 and co-stimulatory antibodies 124,125 targeting CD40, 126 or the STINGVAX vaccine, a cellular vaccine engineered to secrete colony-stimulating factor 2 (CSF2, best known as GM-CSF), 127 plus an immune checkpoint blocker targeting programmed cell death 1 (PDCD1, best known as PD-1), [128][129][130] and (3) mouse CT26 colorectal carcinoma treated with the STINGVAX vaccine plus a PD-1 blocker. 128,130 However, natural CDNs are rapidly degraded by circulating and cell-bound enzymes, including ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), 131 calling for the development of molecules with improved stability for clinical applications.…”

Section: Sting Signaling In Preclinical Tumor Modelsmentioning

confidence: 99%

Trial watch: STING agonists in cancer therapy

et al. 2020

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Stimulator of interferon response cGAMP interactor 1 (STING1, best known as STING) is an endoplasmic reticulum-sessile protein that serves as a signaling hub, receiving input from several pattern recognition receptors, most of which sense ectopic DNA species in the cytosol. In particular, STING ensures the production of type I interferon (IFN) in response to invading DNA viruses, bacterial pathogens, as well as DNA leaking from mitochondria or the nucleus (e.g., in cells exposed to chemotherapy or radiotherapy). As a type I IFN is critical for the initiation of anticancer immune responses, the pharmaceutical industry has generated molecules that directly activate STING for use in oncological indications. Such STING agonists are being tested in clinical trials with the rationale of activating STING in tumor cells or tumor-infiltrating immune cells (including dendritic cells) to elicit immunostimulatory effects, alone or in combination with a range of established chemotherapeutic and immunotherapeutic regimens. In this Trial Watch, we discuss preclinical evidence and accumulating clinical experience shaping the design of Phase I and Phase II trials that evaluate the safety and preliminary efficacy of STING agonists in cancer patients.

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Targeting STING pathways for the treatment of cancer

Cited by 18 publications

References 11 publications

Decreased expression of STING predicts poor prognosis in patients with gastric cancer

Decreased expression of STING predicts poor prognosis in patients with gastric cancer

Versatile modes of cellular regulation via cyclic dinucleotides

Trial watch: STING agonists in cancer therapy

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