#cGAS DNA Sensing Pathway

[colinwilson11]

The cGAS-STING Pathway: A Key Immune Surveillance Mechanism

The innate immune system provides the first line of defense against invading pathogens like viruses and bacteria. One of its key mechanisms for detecting microbial infections is the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. This cellular surveillance pathway plays a critical role in detecting foreign DNA from invading microbes and mounting appropriate immune responses.

How It Works

When microbial DNA enters the cytosol of host cells, it is recognized by the cGAS enzyme. cGAS has the unique ability to bind to DNA and produce the second messenger cyclic GAMP (cGAMP) from ATP and GTP. cGAMP then acts as a ligand to bind and activate the endoplasmic reticulum-associated adaptor protein called STING.

Activation of STING leads to its association with tumor necrosis factor receptor-associated factor 3 and 6 (TRAF3/6). This triggers a downstream signaling cascade involving the protein kinases TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3).

Phosphorylation of IRF3 by TBK1 causes IRF3 dimerization and translocation into the host cell nucleus. There, IRF3 induces the expression of Type I interferons (IFN-α and IFN-β) and other proinflammatory cytokines that signal the presence of invading pathogens to other cells and recruit additional immune defenses.

Role In Antiviral Defense

The cGAS-STING Pathway plays a critical role in the host defense against various DNA viruses like herpes simplex virus 1, cytomegalovirus, Epstein-Barr virus, vaccinia virus and HIV. Upon viral DNA entry in the cytosol, cGAS binds and activates STING to induce Type I IFN production. This initiates an antiviral state in infected cells and neighboring uninfected cells to limit viral replication and spread. Mice lacking cGAS or STING exhibit impaired IFN responses and increased susceptibility to infection by these DNA viruses.

Protecting Against Cancer

Aside from fighting infections, the cGAS-STING Pathway also acts as a tumor suppressor mechanism by detecting aberrant genomic DNA in cancer cells. Many cancer cells have disruptions like broken DNA strands that could lead to cell death if sensed by the immune system. However, cancer cells often develop ways to evade this cGAS-STING surveillance.

Studies have shown that loss of or reduced expression and activity of cGAS or STING promotes tumorigenesis in various cancer types like colon cancer and prostate cancer. At the same time, therapeutically activating the cGAS-STING Pathway seems to stimulate antitumor immunity and enhance the effectiveness of cancer immunotherapies in mouse models. This highlights the pathway's potential for developing new immunotherapeutic strategies against cancer.

Role In Autoimmune Disease

While the cGAS-STING Pathway protects against infections and tumors, its overactivation can also lead to inflammatory and autoimmune conditions. Defects that cause constitutive STING signaling have been linked to autoinflammatory diseases. Genetic mutations that make STING hyperactive and uncontrollable result in a group of rare hereditary inflammatory syndromes known as STING-associated vasculopathies with onset in infancy (SAVI). Patients with SAVI exhibit symptoms resembling systemic lupus erythematosus due to excess Type I IFN production.

Meanwhile, environmental and endogenous cytosolic DNA from dying cells have been shown to aberrantly trigger the cGAS-STING Pathway and IFN responses during conditions like systemic lupus erythematosus or Aicardi-Goutières syndrome. Figuring out ways to modulate cGAS-STING activation or signaling may yield new therapeutic approaches for these diseases.

Pharmaceutical Applications

Given its crucial contribution to antiviral immunity and cancer immunosurveillance, the cGAS-STING Pathway represents an attractive target for pharmaceutical intervention. Small molecule drugs that activate cGAS or STING are being developed as potential antiviral and anticancer agents. STING agonists administered alone or in combination with checkpoint inhibition immunotherapy show promise in treating solid tumors in clinical trials.

Moreover, cGAS or STING inhibitors may offer new ways to treat autoinflammatory conditions caused by overactive cGAS-STING signaling. Researchers continue working to refine drugs that can selectively modulate different points along the pathway for optimal therapeutic benefit while avoiding side effects. As understanding of this defense mechanism deepens, more opportunities may arise to harness it against an array of diseases with immunological underpinnings.

The cGAS-STING Pathway serves as a critical surveillance system helping our innate immune defenses detect cytosolic DNA. Its ability to sense microbial as well as aberrant self-DNA makes it an important regulator of antiviral immunity, tumor suppression, and inflammatory balance. Ongoing investigations into modulating cGAS-STING activation hold promise for developing new immunotherapies targeting infections, cancer, and autoimmune disorders.

Get more insights on this topic:   https://www.ukwebwire.com/role-of-cgas-sting-pathway-in-detecting-cytosolic-dna/

Author Bio:

Alice Mutum is a seasoned senior content editor at Coherent  Insights, leveraging extensive expertise gained from her previous role as a content writer. With seven years in content development, Alice masterfully employs SEO best practices and cutting-edge digital ing strategies to craft high-ranking, impactful content. As an editor, she meticulously ensures flawless grammar and punctuation, precise data accuracy, and perfect alignment with audience needs in every research report. Alice's dedication to excellence and her strategic approach to content make her an invaluable asset in the world of  insights. (LinkedIn: www.linkedin.com/in/alice-mutum-3b247b137 )

*Note: 1. Source: Coherent  Insights, Public sources, Desk research 2. We have leveraged AI tools to mine information and compile it

[jhavelikes]

Neuroinflammation is associated with poor outcomes in patients with spinal cord injury (SCI). Recent studies have demonstrated that stimulator of interferon genes (Sting) plays a key role in inflammatory diseases. However, the role of Sting in SCI remains unclear. In the present study, it is found that increased Sting expression is mainly derived from activated microglia after SCI. Interestingly, knockout of Sting in microglia can improve the recovery of neurological function after SCI. Microglial Sting knockout restrains the polarization of microglia toward the M1 phenotype and alleviates neuronal death. Furthermore, it is found that the downregulation of mitofusin 2 (Mfn2) expression in microglial cells leads to an imbalance in mitochondrial fusion and division, inducing the release of mitochondrial DNA (mtDNA), which mediates the activation of the cGas-Sting signaling pathway and aggravates inflammatory response damage after SCI. A biomimetic microglial nanoparticle strategy to deliver MASM7 (named MSNs-MASM7@MI) is established. In vitro, MSNs-MASM7@MI showed no biological toxicity and effectively delivered MASM7. In vivo, MSNs-MASM7@MI improves nerve function after SCI. The study provides evidence that cGas-Sting signaling senses Mfn2-dependent mtDNA release and that its activation may play a key role in SCI. These findings provide new perspectives and potential therapeutic targets for SCI treatment.

Cytoplasmic Escape of Mitochondrial DNA Mediated by Mfn2 Downregulation Promotes Microglial Activation via cGas‐Sting Axis in Spinal Cord Injury - Wei - 2024 - Advanced Science - Wiley Online Library

[tumimmtxpapers]

Targeting the loss of cGAS/STING signaling in cancer

The cGAS/STING pathway provides a key host defense mechanism by detecting the accumulation of cytoplasmic double-stranded DNA (dsDNA) and mediating innate and adaptive immune signaling. In addition to detecting pathogen-derived dsDNA, cGAS senses intrinsic dsDNA, such as those associated with defective cell cycle progression and mitophagy that has leaked from the nucleus or mitochondria, and subsequently evokes host immunity to eliminate pathogenic cells. In cancer cells, dysregulation of DNA... http://dlvr.it/SsWW2z

[sbgridconsortium]

Ancient mediators of innate immunity

Bacteria can become infected by bacteriophages and have developed a range of anti-phage immune pathways to counteract these infections. These pathways are often multi-gene systems encoding proteins that sense and inhibit virion production, and efforts to catalog anti-phage signaling systems in bacteria have revealed that some of these genes share homology with components of eukaryotic immune systems. This suggests that eukaryotes horizontally acquired some innate immune genes from bacteria.

Many components have been identified as homologous between bacteria and humans, including bacterial cyclic-oligonucleotide-based anti-phage signaling systems (CBASS) with human cGAS and STING, and bacterial Viperins and Gasdermins with human Viperin and Gasdermin D. However, SBGrid member Aaron Whiteley and other researchers have been searching for other potential components in bacterial anti-phage signaling systems which could be homologous to immune signaling elements in humans. The researchers demonstrate that bacteria express anti-phage proteins containing a NACHT module, which is an important element of the animal nucleotide-binding domain leucine-rich repeat containing gene family called NLRs. These NACHT proteins are widespread in bacteria and contain a C-terminal sensor, central NACHT module, and N-terminal effector component, acting against both DNA and RNA bacteriophages. 

Above: Previously reported structure of NLR family CARD domain-containing protein 4. CC BY SBGrid.

Importantly, they determined that mutations in human NLR which lead to stimulus-independent activation of downstream signaling also activate bacterial NACHT proteins, suggesting that the bacterial and human systems share similar signaling mechanisms. This work identifies NACHT module-containing proteins as ancient innate immune signaling elements and expands our knowledge of homology between bacterial anti-phage immune pathways and eukaryotic immune systems.

Read more about this work in Cell.

[jobrxiv]

Postdoc Positions in Cancer Genetics, Genomics, and Immunology University of Texas Southwestern Medical Center Application Deadline: 2022-12-06 Postdoctoral positions are available in the laboratories of Drs. Zhijian ‘James’ Chen lab and Sihan Wu at UT Southwestern Medical Center. Postdocs recruited via this pathway will be housed and supported in the Chen lab in the Molecular Biology department, and co-mentored by Dr. Wu at the Children’s Research Institute. The Chen lab studies innate immune sensing and signaling of nucleic acids, focusing on the cGAS-STING pathway of cytosolic DNA sensing. This pathway has been shown to be important for many physiological and pathological processes. The lab is interested in dissecting the signaling mechanisms of the cGAS pathway as well as its role in immune defense against tumor development. The Wu lab studies the molecular functions and molecular dependencies of extrachromosomal DNA (ecDNA) in human cancer, including its replication, segregation, transcription, and repair, with an aim to develop effective approaches to tackle these mechanisms to eliminate ecDNA in cancer as therapeutic ... See the full job description on jobRxiv: https://jobrxiv.org/job/university-of-texas-southwestern-medical-center-27778-postdoc-positions-in-cancer-genetics-genomics-and-immunology/?feed_id=25105 #ScienceJobs #hiring #research

[rootsanalysis]

In recent years, promising insights from research on the cytosolic DNA sensing (cGAS -STING) pathway has caused a lot of enthusiasm within medical science community. Basically, the STING pathway offers an alternative approach to harnessing the immune system, in order to pharmacologically treat a number of clinical conditions, including oncological and autoimmune disorders. The aforementioned therapeutic benefits can be achieved using modulators of the STING / cGAS-pathway. Over the years, a number of such modulators, capable of either activating or downregulating the STING pathway, have been developed. More than 50 experimental interventions based on this relatively novel concept are currently being developed for the treatment of oncological, autoimmune and inflammatory disorders.

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https://www.rootsanalysis.com/reports/sting-pathway-targeting-therapeutics-and-technologies-market.html

[juniperpublisherscellscienc-blog]

Development of Enpp1 Inhibitors as a Strategy to Activate Stimulator of Interferon Genes (STING) in Cancers and Other Diseases- Juniper Publishers

Abstract

Ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1/NPP1) is a membrane-bound nucleotide metabolizing enzyme that is implicated in a variety of physiological and pathological conditions. Recently, ENPP1 was discovered as the dominant 2’3’-cGAMP hydrolyzing enzyme. 2’3’-cGAMP is the endogenous STING agonist, generated from breakdown of cytosolic DNA by cGAS. Hydrolysis resistant 2’3’-cGAMP’s have been demonstrated to be potent activators of STING-dependent innate immunity and these are currently undergoing clinical trials in cancer. Here we discuss ENPP1 as a potential therapeutic target for activation of STING-dependent innate immune response.

Keywords: Innate immunity; STING; ENPP1/NPP1; Cytokines; Immunotherapies; Interferon; T-cell priming

Introduction

Innate immunity is the first response in the human body against pathogenic, or disease-causing stimuli. These stimuli can vary, and include viruses, perturbed normal tissue, and dying cancer cells. It is an important response, as it prevents continued proliferation of these pathogens and maintains a state of homeostasis within the body. It can also accommodate the development of a specific induced immune response during the first, or primary infection and, can therefore, establish inflammatory conditions. This induced response is specific because of the many different expressions that the cell surface gives off in the form of pattern recognition receptors, which can identify many of the molecules of life, such as, polysaccharides, glycoproteins, glycolipids, and nucleic acids [1].

The definition of innate immunity has altered over time. In earlier years, it was believed that innate immune response was premeditated. However, recent studies have shown that innate immunity is actually a specific response that results from damage or pathogen-associated molecular patterns (DAMP/PAMPs) [2]. In the initial phase, the innate immune system is able to coordinate inflammatory responses through cells of the hematopoietic compartment (neutrophils, macrophages and monocytes) and create conditions suitable for microbial clearance. In the second phase, other cells like dendritic cells are able to process antigens and present them on the surface in concert with major histocompatibility complex (MHC) to prime T-cells. This also allows the body to more effectively fight against infections of the same or similar type in the future. This “memory” is dependent on two specific types of cells: natural killer (NK) cells and macrophages. These cells provide crucial protection against reinfection in the immune system [3]. This “memory” found in innate immune systems is present in both vertebrate and invertebrate organisms.

Cytokines in Innate Immune Response

Cytokines are possibly the most indispensable component of the innate immune response. Cytokines are secreted by cells of the immune system and facilitate interaction between different types of cells. There are many different types of cytokines, and they are classified mainly by their biological functions. The main types of cytokines are: interferons (INFs), interleukins (ILs), transforming growth factors (TGFs), and tumor necrosis factors (TNFs) [4]. Interferons are the most commonly found type of cytokine in vertebrates and mammals and are crucial to mediate antiviral defense. To date, there have been three types of interferons discovered in vertebrates, and specifically mammals: Types 1, 2 and 3. Type 1 IFNs typically facilitate the antiviral response against microbial infection-causing pathogens. Type 2 IFNs also facilitate antiviral response, but at the same time, vitalize the process of phagocytosis and inhibit cell growth. Type 3 IFNs have been demonstrated to be strikingly similar in function to Type 1 IFNs [5,6]. Interleukins are a type of cytokines that also facilitate inflammatory responses in the immune system and help to stimulate cell growth [7]. Transforming growth factors (TGFs) regulate cell growth, help stimulate the growth of oocyte cells (which are found in the ovum), repair wounds inflicted upon the body, participate in immunosuppression, or reduce the activity of the immune system when naturally required [8]. Finally, tumor necrosis factors (TNFs) help to stimulate macrophages as they participate in the biological process of phagocytosis [9].

STING (Stimulator of interferon genes) as a DNA sensor

STING has been identified as a major signaling molecule that plays a pivotal role in innate immune response by inducing the production of interferons. STING is a cytoplasmic pattern recognition receptor activated by nucleic acid ligands known as cyclic dinucleotides (CDNs). These CDNs are generated by the DNA sensor cyclic GMP-AMP synthase (cGAS) using cytosolic DNA from extrinsic pathogens or endogenous aberrant self-DNA [10-12]. In case of tumors, it is probable that dying tumor cells are sources of dsDNA in the cytoplasm. In addition to CDN’s, STING can directly sense DNA and this dual sensing has been uncoupled with specific mutations in STING [10]. Activation of STING induces its binding with a kinase TBK1 (TANK-binding kinase 1) and further phosphorylation and dimerization of IRF3 (Interferon regulatory factor 3). IRF3 and another transcription factor that is activated by STING (STAT6) translocate to nucleus and bind to interferon promoters leading to production of type I interferons.

It is suggested that STING pathway is the main innate immune sensing pathway within tumor microenvironment and the main cell types in the tumor microenvironment that produce type I interferons are the dendritic cells [13,14]. In addition to the activation of STING pathway in response to tumor-derived DNA, dendritic cells prime T-cells by presenting tumor- associated antigens. These effects then create a signaling pathway, which allows T-cells, a main feature of the active immune response, to neutralize tumor cells [15,16]. Some tumor cells are able to “disguise” themselves to the innate immune response by upregulating immune checkpoints, or by having a lack of innate immune response within the tumor. A recent study reported that STING is epigenetically silenced in some cancers [17]. Additionally, oncoproteins from viruses such as human papillomavirus can bind and block activation of STING [18]. Thus, a cytosolic DNA sensing pathway is important for activation of innate immune response. In recent years, there has been considerable interest in the field of immune-oncology as well as an increase in the number of immunotherapies available [19,20].

ENPP1(Ectonucleotide Pyrophosphatase/Phosphodiesterase- 1) And Its Role in Innate Immunity

ENPP1 is a membrane bound enzyme that is an important regulator of extracellular inorganic pyrophosphate in osteoblasts and chondrocytes [21]. It is essential for prevention of soft tissue mineralization and ENPP1 deficient mice can have abnormal gait and progressive calcification in ectopic sites [22]. ENPP1 is responsible for hydrolysis of extracellular nucleotide triphosphates to produce inorganic pyrophosphates (PPi) [23]. Recent investigations have shown that ENPP1 plays a much larger role in limiting the innate immune response of the human body. It has been discovered that STING pathway is regulated by ENPP1[24]. ENPP1 was identified as the major hydrolase for the most potent endogenous CDN ligand for STING: 2’3’-cGAMP [25]. Importantly, it was demonstrated that denaturation of 2’3’-cGAMP can control the activation of the STING pathway [26]. Phosphothioate analogs of 2’3’-cGAMP resistant to ENPP1- mediated hydrolysis potently activate STING [25] and mediate anti-tumor responses. These analogs have now entered clinical trials as intra-tumoral injections in various advance cancers (Figure 1).

In another study, it was shown that Mycobacterium tuberculosis evades host immune response through a bacterial phosphodiesterase (CdnP) which inactivates host 2’3’-cGAMP. Loss of ENPP1 attenuated Mycobacterium tuberculosis infection, as did the inhibition of CdnP, the phosphodiesterase of Mycobacterium tuberculosis [27] More recently, inactivation of porcine ENPP1 was shown to attenuate pseudorabies infection through an interferon-β dependent response [28]. Many viruses generate antagonist proteins that can inactivate cGAS-STING pathway [29]. ENPP1 is differentially expressed in immune cells with low levels in NK cells, DC and macrophages and high levels in neutrophils [30]. ENPP1 is also expressed in a small subset of B-cells and studies suggest that these cells may be involved in modulation of T-cell activity [31]. Interestingly, ENPP1 expression was reported to be elevated in the M2 subtype of macrophages that are known to play a role in tumor promotion [28,32,33]. Other studies have indicated that expression of ENPP1 is increased in astrocytic tumors, breast cancers, and head and neck cancers [34-36]. Thus, inhibition of ENPP1 in humans may provide opportunities for treatment of cancers and pathogenic infections.

Challenges in Development of Inhibitors of ENPP1 for Human Use

Given the various functions for ENPP1 in regulating host immune responses, there is interest in development of ENPP1 inhibitors for human use. These inhibitors may have promising activity in human cancers and infectious pathologies. There are various practical challenges in development of these inhibitors. ENPP1 is a type II transmembrane glycoprotein that belongs to a family of ectonucleotide pyrophosphatase/phosphodiesterase (Enpp) family and consist of seven distinct proteins with distinct functions [37]. Thus, any inhibitor strategy will have to consider development challenges for specificity. In the published crystal structure of mouse ENPP1, there are important structural differences between ENPP2 and ENPP1. The N-terminal somatomedin-like (SMB) domains of ENPP1 do not interact with catalytic domains unlike those in ENPP2 [38,39]. ENPP1 appears to lack a hydrophobic pocket in contrast to ENPP2 although interdomain interactions are preserved [37-40]. Despite these challenges, our group and others have described novel selective and orally bioavailable inhibitors of ENPP1 [41-45].

Fundamental effects of ENPP1 inhibition on host immune response are still being determined. It is not known, for instance, if ENPP1 deficiency in mouse models impairs anti-tumor growth. Thus, optimal duration and intensity of ENPP1 inhibition is still being developed. This is important since systemic administration of these inhibitors can cause unwanted side effects due to excessive release of interferons. Interestingly, ENPP1 knockout mice are viable, thus pointing to possible avenues for development of such inhibitors. Prolonged administration of ENPP1 inhibitors may lead to unwanted effects on bony tissues and ectopic calcifications although this has been disputed in various studies in literature [46]. This is because bone and cartilage effects may not be entirely mediated by ENPP1. In other studies, oral administration of pyrophosphate can attenuate the connective tissue calcifications mediated by ENPP1 mutations in mouse models [47].

Conclusion

As hyper-activation of STING pathway may lead to production of abnormally high levels of proinflammatory cytokines, it is necessary to develop therapeutics that target STING pathway indirectly. Inhibition of ENPP1 activity is one approach that may result in optimal activation of STING pathway, enough to have anti-tumor effects, and minimize unintended consequences. Given the role of ENPP1 in immune modulation and tumor promotion, there is an increased interest to develop novel therapies based on inhibition of the ENPP1 activity and this will emerge as an interesting area in the coming years.

Acknowledgments

We thank Dr. Hariprasad Vankayalapati for advice in developing this review.

https://juniperpublishers.com/ijcsmb/IJCSMB.MS.ID.555655.php

For more Open access journals please visit our site: Juniper Publishers 

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[swissforextrading]

Cell senescence is regulated by innate DNA sensing

31.07.17 - EPFL scientists have made new insights into the control of cell senescence, which is intimately linked to the development of cancer and ageing. Cells in the body or in cultures eventually stop replicating. This phenomenon is called “senescence” and is triggered by shortening of telomeres, oxidative stress or genetic damage to the cells, either acute or simply due to the cell growing “old”. Understanding the causes and impact of senescence can give us deep insights into the development of cancer and ageing. EPFL scientists have now discovered that a DNA-sensing mechanism of the innate immune system — which is pivotal for the immediate defense against pathogens — controls cellular senescence. The work is published in Nature Cell Biology, and highlights potential novel anti-tumor and perhaps anti-ageing strategies. When cells senesce, they undergo profound changes, including the secretion of several inflammation-mediating proteins (cytokines, chemokines, extracellular-matrix proteins, growth factors). The production of this “senescence-associated secretory phenotype” controls a number of biological processes such as wound healing and tissue repair, but also tumor formation and some age-related disorders. But although we know how senescence increases the activity of the genes for these proteins, we know very little about how the entire process begins in the first place. The lab of Andrea Ablasser at EPFL found that senescing cells use a mechanism of the innate immune system to regulate the secretion of inflammation-mediating molecules. The innate immune system includes fast-acting but non-specialized cells (macrophages, neutrophils, mast cells etc.) that provide the first line of defense against the millions of potential pathogens to which humans are constantly exposed.  The innate immune cells use a host of pattern recognition receptors to sense and identify foreign parts of an invading pathogen, such as the DNA of a virus. DNA-sensing is accomplished through a two-receptor system comprising an enzyme called cGAS and an adaptor molecule called STING. Once activated, the cGAS-STING pathway triggers the production of inflammatory proteins that help fight off the pathogen.  Unexpectedly, the researchers now found that senescent cells in the body use the cGAS-STING pathway to regulate and facilitate their secretion of inflammation mediators. But in the context of senescent cells, it is the cell’s own DNA that activates cGAS because of defects in the integrity of the nuclear envelope. Examining the relevance of this fundamental mechanism, the study found that the cGAS-controlled secretion of cytokines appears to play a role in various contexts of senescence such oxidative stress, oncogene signaling and irradiation. The scientists also observed that at least irradiation and oncogene activation exert these actions through cGAS-STING in vivo as well.  The study shows that DNA sensing through the cGAS-STING pathway is an important regulator of senescence and the release of inflammatory mediators, and could also serve as surveillance system that protects the organism against neoplastic cells, which opens up new insights for our understanding of the development of cancer. Moreover, since the inflammatory response of senescent cells also promotes ageing, the cGAS-STING pathway could serve as new drug target to tackle age-related diseases. --- Collaborating institutes * EPFL Core Facilities (BBCF, BIOp, CPG, FCCF, GECF) * University Hospital Tübingen * University of Oxford Funding * Swiss National Science Foundation * Gebert-Rüf Stiftung * European Molecular Biology Organization (EMBO) Reference Selene Glück, Baptiste Guey, Muhammet Fatih Gulen, Katharina Wolter, Tae-Won Kang, Niklas Arndt Schmacke, Anne Bridgeman, Jan Rehwinkel, Lars Zender, Andrea Ablasser. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nature Cell Biology 31 July 2017. DOI: 10.1038/ncb3586 Nik Papageorgiou http://actu.epfl.ch/news/cell-senescence-is-regulated-by-innate-dna-sensing (Source of the original content)

[colinwilson11]

The cGAS-STING Pathway plays a crucial role in host defense against cytoplasmic DNA from invading pathogens. When double-stranded DNA is present in the cytoplasm, which is not normal, it activates the enzyme cyclic GMP-AMP synthase or cGAS. cGAS acts as a DNA sensor that detects cytosolic DNA and produces the second messenger cyclic GMP-AMP (cGAMP) from GTP and ATP.

[cancersfakianakis1]

PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness

PARP inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2-mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of ssDNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations. PARPi promoted accumulation of cytosolic DNA fragments because of unresolved DNA lesions, which in turn activated the DNA-sensing cGAS–STING pathway and stimulated production of type I IFNs to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade.Significance:This work uncovers the mechanism behind the clinical efficacy of PARPi in patients with both BRCA-wild-type and BRCA-mutant tumors and provides a rationale for combining PARPi with immunotherapy in patients with cancer. http://bit.ly/2Cxvze3

[tumimmtxpapers]

Activation of dendritic cells by targeted DNA: a potential addition to the armamentarium for anti-cancer immunotherapy.

Related Articles Activation of dendritic cells by targeted DNA: a potential addition to the armamentarium for anti-cancer immunotherapy. Cancer Immunol Immunother. 2019 Sep 26;: Authors: Fyrstenberg Laursen M, Kofod-Olsen E, Agger R Abstract In the past decade, remarkable progress has been made in immunotherapy against cancer. Specifically, the introduction of immune checkpoint inhibitors has revolutionized the field. However, many patients are unable to benefit significantly from this treatment option. One of the major reasons for this is most likely the absence of an adequate tumor-specific T cell response in these patients. A way to circumvent this problem might be to combine immune checkpoint inhibitor treatment with new strategies to activate tumor-specific T cells. One such strategy could be to activate and mature dendritic cells in situ. Dendritic cells carry an array of external and internal pattern recognition receptors that induce cell activation and maturation when interacting with their corresponding damage-associated or pathogen-associated molecular patterns (DAMPs or PAMPs). Targeting such molecular patterns directly to dendritic cells might be a way to evoke stronger immune responses. Here, we review our recent findings using antibody-targeted DNA. We summarize the results from our experiments showing that dendritic cells can be actively targeted in vivo through the αXβ2 integrin subunit CD11c, and that DNA delivered through this receptor in vitro leads to maturation of dendritic cells via the cytosolic cGAS/STING DNA-sensing pathway. PMID: 31559451 [PubMed - as supplied by publisher] http://dlvr.it/RF5plt

[jobrxiv]

Postdoc Positions in Cancer Genetics, Genomics, and Immunology University of Texas Southwestern Medical Center Application Deadline: 2022-12-06 Postdoctoral positions are available in the laboratories of Drs. Zhijian ‘James’ Chen lab and Sihan Wu at UT Southwestern Medical Center. Postdocs recruited via this pathway will be housed and supported in the Chen lab in the Molecular Biology department, and co-mentored by Dr. Wu at the Children’s Research Institute. The Chen lab studies innate immune sensing and signaling of nucleic acids, focusing on the cGAS-STING pathway of cytosolic DNA sensing. This pathway has been shown to be important for many physiological and pathological processes. The lab is interested in dissecting the signaling mechanisms of the cGAS pathway as well as its role in immune defense against tumor development. The Wu lab studies the molecular functions and molecular dependencies of extrachromosomal DNA (ecDNA) in human cancer, including its replication, segregation, transcription, and repair, with an aim to develop effective approaches to tackle these mechanisms to eliminate ecDNA in cancer as therapeutic ... See the full job description on jobRxiv: https://jobrxiv.org/job/university-of-texas-southwestern-medical-center-27778-postdoc-positions-in-cancer-genetics-genomics-and-immunology/?feed_id=22660 #ScienceJobs #hiring #research

[colinwilson11]

The Rise Of CGAS-STING Pathway Market Therapies Will Lead To A Revolution In Cancer Immunotherapy

The CGAS-STING pathway market will grow at the highest pace owing to increasing R&D and growing potential of nucleic-acid sensing pathway modulators in cancer immunotherapy. The innate immune system recognizes nucleic acid species unique to pathogens via cytosolic DNA sensors and mediates type I interferon (IFN) responses that are critical for anti-viral immunity. Of these sensors, the cGAS-STING pathway couples cytosolic DNA sensing to type I IFN induction and downstream transcriptional programs. Once activated, cGAS produces the second messenger cyclic GMP-AMP (cGAMP) which binds and activates stimulator of IFN genes (STING). This signals the activation of downstream IFN regulatory factor 3 (IRF3) and NF-κB, leading to production of type I IFNs and pro-inflammatory cytokines.

The CGAS STING Pathway Market is estimated to be valued at US$ 0.46 Bn in 2024 and is expected to exhibit a CAGR of 25.% over the forecast period 2024-2031.

Growing significance of immunotherapy in cancer treatment and the advantages of targeting the cGAS-STING pathway such as involvement in sensing tumor DNA in the cytoplasm and activation of potent antitumor immunity has augmented the demand of associated drugs and therapies. The success of immunotherapy approaches has led to substantial investment in nucleic acid-sensing pathway modulators by pharmaceutical companies.

Key Takeaways

Key players operating in the cGAS-STING pathway are IFM Therapeutics, Bristol-Myers Squibb, Novartis, AstraZeneca, Merck & Co. Companies are investing heavily in R&D to develop novel therapeutics targeting this pathway. For instance, IFM Therapeutics is developing first-in-class STING agonist focusing on liver and gastrointestinal cancers in phase I/II clinical trial.

The demand for cGAS-STING therapies is increasing rapidly mainly due to growing demand for innovative cancer immunotherapies. According to American Cancer Society, around 1.9 million new cancer cases are diagnosed in the US annually presenting massive market potential. Additionally, improving accessibility of immunotherapy in developing countries will further drive the demand.

Advancements in understanding molecular mechanisms of cGAS-STING pathway activation and development of novel agonist and modulators have expanded therapeutic applications. Ongoing research for developing vaccines and combination therapies with checkpoint inhibitors holds promise to revolutionize cancer treatment through innate immunity activation.

Market Trends

Combination therapies research: There is growing focus on exploring synergies of cGAS-STING agonists with other immunotherapies like checkpoint inhibitors. Ongoing clinical trials evaluating combinations are demonstrating encouraging response rates.

Personalized medicine approach: Efforts are being made to develop biomarkers to predict response and identify patients likely to benefit from cGAS-STING therapies. This personalized approach can improve clinical outcomes.

Geographical expansion: Major players are expanding manufacturing and clinical trials to countries like China and India having huge patient pools. This will boost accessibility and commercialization prospects.

Market Opportunities

First STING agonist approval: IFM Therapeutics' lead molecule will be the first STING agonist examined in registrational trials paving way for first approval in 2026-27.

 Increased adoptability: As clinical evidence demonstrating benefits of cGAS-STING modulation emerges, adoption rate in treatment guidelines and clinical practice is expected to surge exponentially.

New therapeutic areas: Preliminary evidence shows cGAS-STING pathway also plays a role in autoimmune diseases providing scope for therapies in indications beyond oncology.

Impact Of COVID-19 On CGAS STING Pathway Market Growth

The COVID-19 pandemic has profoundly impacted the CGAS STING Pathway Market. During the initial outbreak in early 2020, the market recorded a decline as research activities slowed down and clinical trials faced interruptions due to lockdowns and social distancing norms. However, with shifting focus on immune therapies for tackling novel coronavirus infections, the interest in CGAS STING pathway modulators witnessed rapid growth. Many companies expedited their programs related to IFN activation via cGAS-STING pathway to develop host-directed antiviral therapies against SARS-CoV-2. The pandemic highlighted the need for developing strategies to strengthen innate immune responses via cGAS-STING pathway modulation. While clinical studies faced delays in 2020, collaborations between industry and research institutes intensified to advance immunotherapies targeting this pathway. Moving forward, the high growth projected for this market is expected to accelerate further on the back of strong ongoing research to evaluate potential of cGAS-STING pathway modulators as adjuvant or monotherapy for COVID-19.

Regional Concentration Of CGAS STING Pathway Market

North America currently dominates the CGAS STING Pathway Market and holds over 40% of the global market share in terms of value. This is due to high immunotherapies R&D spending and strong presence of key market players in the US. Moreover, the region is an early adopter of novel immune mechanisms and immune-oncology approaches. Within North America, the United States represents the most lucrative market owing to significant research funding and growing clinical adoption of STING agonists. On the other hand, Asia Pacific region is projected to witness the fastest growth during the forecast period with a CAGR of over 30%. This impressive growth can be attributed to rising healthcare expenditure, expanding clinical research infrastructure and growing focus of global pharma companies on emerging Asian markets. China and India are expected to spearhead the growth of CGAS STING Pathway Market in Asia Pacific region.

Europe currently represents the second largest regional market for CGAS STING pathway modulators globally. Availability of latest healthcare technologies, sophisticated research infrastructure and presence of major industry players have aided the growth of CGAS STING Pathway Market in Europe. Within the region, Germany, United Kingdom and France together hold around half of the total European market in terms of value. However, Eastern Europe is estimated to depict the fastest gains owing to increasing government spending to strengthen native research capabilities. Moreover, growing collaborations between European and US pharmaceutical firms will further stimulate market growth during the forecast period.

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What Are The Key Data Covered In This CGAS STING Pathway Market Report?

:- Market CAGR throughout the predicted period

:- Comprehensive information on the aspects that will drive the CGAS STING Pathway Market's growth between 2024 and 2031.

:- Accurate calculation of the size of the CGAS STING Pathway Market and its contribution to the market, with emphasis on the parent market

:- Realistic forecasts of future trends and changes in consumer behaviour

:- CGAS STING Pathway Market Industry Growth in North America, APAC, Europe, South America, the Middle East, and Africa

:- A complete examination of the market's competitive landscape, as well as extensive information on vendors

:- Detailed examination of the factors that will impede the expansion of CGAS STING Pathway Market vendors

FAQ’s

Q.1 What are the main factors influencing the CGAS STING Pathway Market?

Q.2 Which companies are the major sources in this industry?

Q.3 What are the market’s opportunities, risks, and general structure?

Q.4 Which of the top CGAS STING Pathway Market companies compare in terms of sales, revenue, and prices?

Q.5 Which businesses serve as the CGAS STING Pathway Market’s distributors, traders, and dealers?

Q.6 How are market types and applications and deals, revenue, and value explored?

Q.7 What does a business area’s assessment of agreements, income, and value implicate?

*Note: 1. Source: Coherent Market Insights, Public sources, Desk research 2. We have leveraged AI tools to mine information and compile it

[cancersfakianakis1]

PARPi triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCAness

Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2 mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of single-stranded DNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations. PARPi promoted accumulation of cytosolic DNA fragments due to unresolved DNA lesions, which in turn activated the DNA sensing cGAS-STING pathway and stimulated production of type I interferons to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade. https://ift.tt/2AvkQQb

[tumimmtxpapers]

KDM5 histone demethylases repress immune response via suppression of STING.

KDM5 histone demethylases repress immune response via suppression of STING. PLoS Biol. 2018 Aug 06;16(8):e2006134 Authors: Wu L, Cao J, Cai WL, Lang SM, Horton JR, Jansen DJ, Liu ZZ, Chen JF, Zhang M, Mott BT, Pohida K, Rai G, Kales SC, Henderson MJ, Hu X, Jadhav A, Maloney DJ, Simeonov A, Zhu S, Iwasaki A, Hall MD, Cheng X, Shadel GS, Yan Q Abstract Cyclic GMP-AMP (cGAMP) synthase (cGAS) stimulator of interferon genes (STING) senses pathogen-derived or abnormal self-DNA in the cytosol and triggers an innate immune defense against microbial infection and cancer. STING agonists induce both innate and adaptive immune responses and are a new class of cancer immunotherapy agents tested in multiple clinical trials. However, STING is commonly silenced in cancer cells via unclear mechanisms, limiting the application of these agonists. Here, we report that the expression of STING is epigenetically suppressed by the histone H3K4 lysine demethylases KDM5B and KDM5C and is activated by the opposing H3K4 methyltransferases. The induction of STING expression by KDM5 blockade triggered a robust interferon response in a cytosolic DNA-dependent manner in breast cancer cells. This response resulted in resistance to infection by DNA and RNA viruses. In human tumors, KDM5B expression is inversely associated with STING expression in multiple cancer types, with the level of intratumoral CD8+ T cells, and with patient survival in cancers with a high level of cytosolic DNA, such as human papilloma virus (HPV)-positive head and neck cancer. These results demonstrate a novel epigenetic regulatory pathway of immune response and suggest that KDM5 demethylases are potential targets for antipathogen treatment and anticancer immunotherapy. PMID: 30080846 [PubMed - as supplied by publisher] http://dlvr.it/Qf4Vpr

[tumimmtxpapers]

Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells.

Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells. Sci Immunol. 2017 May 19;2(11): Authors: Dai P, Wang W, Yang N, Serna-Tamayo C, Ricca JM, Zamarin D, Shuman S, Merghoub T, Wolchok JD, Deng L Abstract Advanced cancers remain a therapeutic challenge despite recent progress in targeted therapy and immunotherapy. Novel approaches are needed to alter the tumor immunosuppressive microenvironment and to facilitate the recognition of tumor antigens that leads to antitumor immunity. Poxviruses, such as modified vaccinia virus Ankara (MVA), have potential as immunotherapeutic agents. We show that infection of conventional dendritic cells (DCs) with heat- or ultraviolet-inactivated MVA leads to higher levels of interferon induction than MVA alone through the cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase)-STING cytosolic DNA-sensing pathway. Intratumoral injection of inactivated MVA (iMVA) was effective and generated adaptive antitumor immunity in murine melanoma and colon cancer models. iMVA-induced antitumor therapy was less effective in STING- or Batf3-deficient mice than in wild-type mice, indicating that both cytosolic DNA sensing and Batf3-dependent CD103(+)/CD8α(+) DCs are essential for iMVA immunotherapy. The combination of intratumoral delivery of iMVA and systemic delivery of immune checkpoint blockade generated synergistic antitumor effects in bilateral tumor implantation models as well as in a unilateral large established tumor model. Our results suggest that inactivated vaccinia virus could be used as an immunotherapeutic agent for human cancers. PMID: 28763795 [PubMed] http://dlvr.it/PbDgzT