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Researchers Focus on Putting the STING Back Into Immune Response

Jane De Lartigue, PhD
Published: Tuesday, Jul 03, 2018
Most anticancer immunotherapies that have reached clinical practice have focused on exploiting T cells, the major effectors of the adaptive immune response, with the goal of provoking an immune memory that leads to dramatic, long-lasting effects.

More recently, immuno-oncologists have turned their attention to the role of the second arm of the immune response—the more rough-and-ready innate arm, which serves as the body’s frontline defense against pathogenic invaders and, it seems, cancer.

Several therapeutic avenues for targeting the cellular and molecular components of innate antitumor immunity are being explored. The stimulator of interferon genes (STING) pathway is generating a particular buzz because it is a main promoter of the type I interferon (IFN) response that is central to innate immunity and often defective in cancer cells. Most excitingly, it bridges the 2 arms of the immune system by priming T cells. Therapeutically targeting the STING pathway could transform an immunologically “cold” tumor into a “hot” one, making it more likely to respond to other forms of immunotherapy, such as immune checkpoint inhibitors.

Many pharmaceutical companies are pursuing STING agonists. Although most of the agents are in preclinical or discovery stages, the first clinical trials are under way in combination with checkpoint blockade agents.

Early Warning System

The innate immune response is the frontline of defense against pathogenic invaders, as well as potentially harmful “self” material. These cellular mediators include natural killer cells, macrophages, neutrophils, and dendritic cells that express receptors encoded by genes inherited though the germline, known as pattern recognition receptors (PRRs).

As their name suggests, these receptors recognize unique molecular patterns found in microorganisms, called pathogen-associated molecular patterns, or components of the host cell that are released during cellular damage or death, called danger-associated molecular patterns (DAMPs). The best-known PRRs are tolllike receptors (TLRs) and C-type lectin receptors, but there are many others, and their engagement depends on the nature of the encountered threat.1

One such threat is foreign nucleic acids; in particular, the microbial and viral DNA that is introduced into the host cell during infection. A potent stimulator of the innate immune response, it triggers the production of type I IFNs (IFN-α and IFN-β) and secretion of proinflammatory cytokines via activation of DNA sensors in the cell’s cytosol.

A vast array of putative cytosolic DNA sensors have been proposed, but how they triggered an IFN response was unclear. In 2008, the STING protein was identified as an essential adapter in this process.

Researchers attempted to link STING to many of these DNA sensors upstream. However, it was not until the discovery in 2013 of a novel DNA sensor, cyclic guanosine monophosphate (GMP)– adenosine monophosphate (AMP) synthase (cGAS), that a clear winner emerged, providing an undisputed biological mechanism by which DNA binding translates into an IFN response.

Other DNA sensors with distinct functions are also well established, but their downstream signaling pathways are poorly understood. These include toll-like receptor (TLR) 9, which predominantly detects endosomal hypomethylated DNA, and sensors of other nucleic acids, such as retinoic acid-inducible gene 1 (RIG-I), TLR7, and TLR8, which detect viral RNA.1-3

Figure 1. Immune Signaling in the STING Pathway

How the STING Pathway Functions

Current understanding of the STING pathway posits that cGAS senses and binds to cytosolic DNA, triggering a conformational change that activates it. Activated cGAS catalyzes the synthesis of cyclic GMP-AMP (cGAMP) from adenosine triphosphate and guanosine triphosphate. A cyclic dinucleotide (CDN), cGAMP functions as a second messenger, binding to and activating STING, which is found on the membrane of the endoplasmic reticulum.

The precise mechanism through which cGAMP activates STING remains somewhat unclear. Current models suggest that STING proteins are found in pairs and that cGAMP binds to a central crevice in the STING dimer, forcing a structural change in the protein that releases a previously hidden tail.

The STING protein moves to the Golgi apparatus and, through its tail, binds to tank-binding kinase 1 (TBK1). TBK1 phosphorylates transcription factors including IRF3 and NFκB, which move into the nucleus and induce the transcription of type I IFN genes (Figure 1).

STING is found in both immune and nonimmune cells. Within the immune system, it is found on cells of both the innate and adaptive arms, including macrophages, antigen-presenting cells, and T cells. On nonimmune cells, it is found on endothelial cells, fibroblasts, and epithelial cells.


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