The Cytosolic DNA-Sensing cGAS–STING Pathway in Cancer

Kwon, John; Bakhoum, Samuel F.

doi:10.1158/2159-8290.cd-19-0761

Cited by 684 publications

(654 citation statements)

References 160 publications

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“…ROS can generate cytosolic DNA, which is sensed by cGAS within tumours. The cGAS, in turn, activates STING to upregulate the expression of type 1 IFN, ISG and SASP genes [224]. The oxidized base 8-hydroxyguanosine (8-OHG), a marker of oxidative damage in DNA, potentiated cytosolic immune recognition by decreasing its susceptibility to repair exonuclease1 (TREX1)-mediated degradation.…”

Section: Reactive Oxygen Species and Nitrogen Speciesmentioning

confidence: 99%

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Ragu

Matos-Rodrigues

Lopez

2020

Genes

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Complete and accurate DNA replication is essential to genome stability maintenance during cellular division. However, cells are routinely challenged by endogenous as well as exogenous agents that threaten DNA stability. DNA breaks and the activation of the DNA damage response (DDR) arising from endogenous replication stress have been observed at pre-or early stages of oncogenesis and senescence. Proper detection and signalling of DNA damage are essential for the autonomous cellular response in which the DDR regulates cell cycle progression and controls the repair machinery. In addition to this autonomous cellular response, replicative stress changes the cellular microenvironment, activating the innate immune response that enables the organism to protect itself against the proliferation of damaged cells. Thereby, the recent descriptions of the mechanisms of the pro-inflammatory response activation after replication stress, DNA damage and DDR defects constitute important conceptual novelties. Here, we review the links of replication, DNA damage and DDR defects to innate immunity activation by pro-inflammatory paracrine effects, highlighting the implications for human syndromes and immunotherapies.Genes 2020, 11, 409 2 of 26 formed when nascent transcripts re-anneal to their template DNA, displacing the non-template strand as single-stranded DNA (ssDNA) [12]. Elevated R-loop levels cause DNA damage and genome instability. The loss of RNA processing and regulatory factors increases R-loop levels, causing R-loop dependent DNA damage in eukaryotic cells [13][14][15][16].DNA breaks and activation of the DNA damage response (DDR), arising from endogenous replication stress, have been observed at early or precancerous stages, and adaptation to replication stress plays an important role in tumour development [17][18][19][20]. The DDR protects genome stability through the precise coordination of a network of pathways, ensuring faithful transmission of genetic material, including DNA replication, repair and recombination, cell cycle checkpoint and chromosome segregation. Ultimately, these autonomous cell responses induce senescence or cell death [21][22][23][24][25]. All these processes prevent the proliferation of cells bearing DNA damage and/or genetic rearrangements. In agreement, syndromes caused by mutations in DDR and/or DNA repair factors are often associated with high genetic instability, cancer predisposition and premature ageing [24,[26][27][28]. In addition to these cell-autonomous responses, protective process(es) also act at the organism level. Such mechanism(s) involve the modification of the cellular microenvironment and ultimately the activation of innate immunity.The inflammatory response is a universal cell-intrinsic response to infections or tissue damage. Inflammation, which is triggered when innate immune cells detect infection, for example, eliminates the initial cause of cell injury, clears out necrotic cells and tissues damaged from the original insult and from the inflammatory process, and initiates ...

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Section: Reactive Oxygen Species and Nitrogen Speciesmentioning

confidence: 99%

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Ragu

Matos-Rodrigues

Lopez

2020

Genes

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“…In general, aberrant cytoplasmic DNA accumulation or micronuclei formation following DNA damaging events are detected by cyclic GMP-AMP synthase (cGAS), which produces the second messenger cyclic GMP-AMP (cGAMP) that directly activates its downstream stimulator of interferon genes (STING) [99]. Activation of STING subsequently induces upregulation of its downstream cytokines, including type I interferon and CXCL10, which promotes T-cell-mediated therapeutic antitumor immunity via enhancing neoantigen presentation and T-cell recruitment into the TME [100]. Not only DNA damage accumulation but also excessive ER stress activate the STING pathway [101].…”

Section: Therapeutic Strategy Targeting Innate Immune Signaling In Rbmentioning

confidence: 99%

Tumor Milieu Controlled by RB Tumor Suppressor

Kitajima

Takahashi

2020

IJMS

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The RB gene is one of the most frequently mutated genes in human cancers. Canonically, RB exerts its tumor suppressive activity through the regulation of the G1/S transition during cell cycle progression by modulating the activity of E2F transcription factors. However, aberration of the RB gene is most commonly detected in tumors when they gain more aggressive phenotypes, including metastatic activity or drug resistance, rather than accelerated proliferation. This implicates RB controls’ malignant progression to a considerable extent in a cell cycle-independent manner. In this review, we highlight the multifaceted functions of the RB protein in controlling tumor lineage plasticity, metabolism, and the tumor microenvironment (TME), with a focus on the mechanism whereby RB controls the TME. In brief, RB inactivation in several types of cancer cells enhances production of pro-inflammatory cytokines, including CCL2, through upregulation of mitochondrial reactive oxygen species (ROS) production. These factors not only accelerate the growth of cancer cells in a cell-autonomous manner, but also stimulate non-malignant cells in the TME to generate a pro-tumorigenic niche in a non-cell-autonomous manner. Here, we discuss the biological and pathological significance of the non-cell-autonomous functions of RB and attempt to predict their potential clinical relevance to cancer immunotherapy.

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“…( 12, 16–18 ) Cancer cells are known to have high levels of cytoplasmic DNA, which results in the constitutive (although still inducible) “basal” activation of the cGAS/STING pathway. ( 19–21 ) The cytosolic DNA comes from a variety of sources including ruptured micronuclei, reactivation of endogenous retroviral sequences, mitochondrial DNA, mitotic defects, etc..( 19–21 ) In contrast, recent work has indicated that the cGAS/STING pathway can also promote metastasis in genetically unstable cells. ( 20, 22 ) Cytoplasmic DNA triggers the constitutive activation of cGAS and STING, however, in this setting IRF3 is not activated.…”

Section: Introductionmentioning

confidence: 99%

Mutant p53 suppresses innate immune signaling to promote tumorigenesis

Ghosh

Saha

Bettke

et al. 2020

Preprint

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29Mutations in the p53 tumor suppressor occur very frequently in human cancer. 30Often, such mutations lead to the constitutive overproduction of mutant p53 31 (mtp53) proteins, which can exert a cancer-promoting gain-of-function (GOF). We 32 have identified a novel mechanism by which mtp53 controls both cell-autonomous 33 and non-cell autonomous signaling to promote cancer cell survival and suppress 34 tumor immune surveillance. Mtp53 interferes with the function of the cytoplasmic 35 DNA sensing machinery, cGAS-STING-TBK1-IRF3, that controls the activation of 36 the innate immune response. We find that mtp53, but not wildtype p53, binds to 37 TANK binding protein kinase (TBK1) and inhibits both its basal and agonist-38 induced activity. The association of mtp53 with TBK1 prevents the formation of a 39 trimeric complex between TBK1-STING-IRF3, which is required for activation, 40 nuclear translocation and transcriptional activity of IRF3. Mtp53 knockdown 41 restores TBK1 activity, resulting in the transcriptional induction of IRF3 target 42 genes and IRF3-dependent apoptosis. Furthermore, inactivation of innate immune 43 signaling by mtp53 alters cytokine production resulting in immune evasion. 44 Restored TBK1 signaling was sufficient to bypass mtp53 and reactivate cell-45 autonomous and non-cell autonomous tumor control. Thus, overriding mtp53's 46 inhibition of this cytosolic DNA sensing pathway may ultimately lead to restored 47 an oncogenic mtp53 protein that exhibits gain-of function activities.(5) Recently, it has been 62 reported that 91% of cancers that have a mtp53 allele have lost their second allele through 63 mutation or chromosomal loss.(6) Furthermore, the presence of mtp53 correlates with increased 64 chromosomal instability leading to loss of tumor suppressor genes and amplification of 65 oncogenes.(6, 7) 66 Aneuploidy is considered one of the hallmarks of cancer and is thought to play an 67 important role in driving tumor cell evolution.(8) Aneuploidy has been shown to provoke cell 68 cycle arrest, senescence, increased pro-inflammatory cytokine production and upregulation of 69 Natural Killer (NK) cell ligands in tumor cells, resulting in their subsequent killing by NK 70 cells.(9) In an in vivo setting, the increased production of pro-inflammatory cytokines coupled 71 with increased NK cell ligand expression permits the recruitment of immune cells and clearance 72 of abnormal cells.(10) Thus, in addition to the cell-autonomous mechanisms that suppress 73 genetic instability, cells also utilize non-cell autonomous mechanisms to signal their own 74 destruction.(9) However, chromosomal instability can give rise to micronuclei, which are prone 75 to rupturing and releasing the DNA into the cytoplasm.(11) DNA leaked into the cytoplasm is 76 recognized by the DNA binding protein, cyclic GMP-AMP synthase (cGAS), which in turn triggers 77 innate immune signaling that results in the production of type I interferons.(12) Mechanistically, 78 DNA promotes cGAS homodimerization and production of the secon...

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The Cytosolic DNA-Sensing cGAS–STING Pathway in Cancer

Cited by 684 publications

References 160 publications

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Tumor Milieu Controlled by RB Tumor Suppressor

Mutant p53 suppresses innate immune signaling to promote tumorigenesis

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