Abstract:The stimulator of interferon genes (STING) cellular signaling pathway is a promising target for cancer immunotherapy. Activation of the intracellular STING protein triggers the production of a multifaceted array of immunostimulatory molecules, which, in the proper context, can drive dendritic cell maturation, antitumor macrophage polarization, T cell priming and activation, natural killer cell activation, vascular reprogramming, and/or cancer cell death, resulting in immune-mediated tumor elimination and gener… Show more
“… 123 IFN-β largely depends on the facilitation effect of the enhanceosome and canonical NF-κB can work in conjunction with IRF-3 as well as other enhancer components to maximize the expression of IFN-β gene. 124 , 125 Abe et al observed a 50% decrease in IFN-β production in primary mouse embryonic fibroblast cells when canonical NF-κB expression was partially silenced via RNA interference (RNAi). 119 Similarly, canonical NF-κB and IRF3 are essential to induce type I IFN in DCs stimulated by irradiated tumor cell after IR.…”
Radiotherapy (RT) is delivered for purposes of local control, but can also exert systemic effect on remote and non-irradiated tumor deposits, which is called abscopal effect. The view of RT as a simple local treatment has dramatically changed in recent years, and it is now widely accepted that RT can provoke a systemic immune response which gives a strong rationale for the combination of RT and immunotherapy (iRT). Nevertheless, several points remain to be addressed such as the interaction of RT and immune system, the identification of the best schedules for combination with immunotherapy (IO), the expansion of abscopal effect and the mechanism to amplify iRT. To answer these crucial questions, we roundly summarize underlying rationale showing the whole immune landscape in RT and clinical trials to attempt to identify the best schedules of iRT. In consideration of the rarity of abscopal effect, we propose that the occurrence of abscopal effect induced by radiation can be promoted to 100% in view of molecular and genetic level. Furthermore, the “radscopal effect” which refers to using low-dose radiation to reprogram the tumor microenvironment may amplify the occurrence of abscopal effect and overcome the resistance of iRT. Taken together, RT could be regarded as a trigger of systemic antitumor immune response, and with the help of IO can be used as a radical and systemic treatment and be added into current standard regimen of patients with metastatic cancer.
“… 123 IFN-β largely depends on the facilitation effect of the enhanceosome and canonical NF-κB can work in conjunction with IRF-3 as well as other enhancer components to maximize the expression of IFN-β gene. 124 , 125 Abe et al observed a 50% decrease in IFN-β production in primary mouse embryonic fibroblast cells when canonical NF-κB expression was partially silenced via RNA interference (RNAi). 119 Similarly, canonical NF-κB and IRF3 are essential to induce type I IFN in DCs stimulated by irradiated tumor cell after IR.…”
Radiotherapy (RT) is delivered for purposes of local control, but can also exert systemic effect on remote and non-irradiated tumor deposits, which is called abscopal effect. The view of RT as a simple local treatment has dramatically changed in recent years, and it is now widely accepted that RT can provoke a systemic immune response which gives a strong rationale for the combination of RT and immunotherapy (iRT). Nevertheless, several points remain to be addressed such as the interaction of RT and immune system, the identification of the best schedules for combination with immunotherapy (IO), the expansion of abscopal effect and the mechanism to amplify iRT. To answer these crucial questions, we roundly summarize underlying rationale showing the whole immune landscape in RT and clinical trials to attempt to identify the best schedules of iRT. In consideration of the rarity of abscopal effect, we propose that the occurrence of abscopal effect induced by radiation can be promoted to 100% in view of molecular and genetic level. Furthermore, the “radscopal effect” which refers to using low-dose radiation to reprogram the tumor microenvironment may amplify the occurrence of abscopal effect and overcome the resistance of iRT. Taken together, RT could be regarded as a trigger of systemic antitumor immune response, and with the help of IO can be used as a radical and systemic treatment and be added into current standard regimen of patients with metastatic cancer.
“…However, 5,6-dimethylxanthenone-4-acetic acid does not activate human STING. Many different CDNs with agonist activity on human STING have been developed and are being evaluated as primary or adjunctive therapy in human cancers (reviewed in refs 8 , 9 ). Unsurprisingly, CDNs have also been used to enhance inflammatory responses and reduce SARS-CoV-2 infection of human bronchial epithelial cells in vitro and mouse cells in vivo 157 .…”
Section: Modulation Of Cgas–sting In Diseasementioning
confidence: 99%
“…For example, activation of cGAS–STING, predominantly by mitochondrial DNA (mtDNA), has been implicated in both acute and chronic kidney disease (CKD) 4 – 7 . However, deep knowledge of the biochemistry of the cGAS–STING cassette has also enabled investigators to harness this pathway to augment immune responses against tumours and reverse cancer-associated immune suppression (reviewed in refs 8 , 9 ). Fig.…”
Cells are equipped with numerous sensors that recognize nucleic acids, which probably evolved for defence against viruses. Once triggered, these sensors stimulate the production of type I interferons and other cytokines that activate immune cells and promote an antiviral state. The evolutionary conserved enzyme cyclic GMP–AMP synthase (cGAS) is one of the most recently identified DNA sensors. Upon ligand engagement, cGAS dimerizes and synthesizes the dinucleotide second messenger 2′,3′-cyclic GMP–AMP (cGAMP), which binds to the endoplasmic reticulum protein stimulator of interferon genes (STING) with high affinity, thereby unleashing an inflammatory response. cGAS-binding DNA is not restricted by sequence and must only be >45 nucleotides in length; therefore, cGAS can also be stimulated by self genomic or mitochondrial DNA. This broad specificity probably explains why the cGAS–STING pathway has been implicated in a number of autoinflammatory, autoimmune and neurodegenerative diseases; this pathway might also be activated during acute and chronic kidney injury. Therapeutic manipulation of the cGAS–STING pathway, using synthetic cyclic dinucleotides or inhibitors of cGAMP metabolism, promises to enhance immune responses in cancer or viral infections. By contrast, inhibitors of cGAS or STING might be useful in diseases in which this pro-inflammatory pathway is chronically activated.
“…4a–c). 16,17,161 For instance, Weissleder et al used β-cyclodextrin nanoparticles to deliver TLR agonists and thus promote macrophage repolarisation. 162 The authors reported that, compared with other molecules tested (CSF1R inhibitor, tyrosine kinase inhibitor, and other TLR7/8 agonists), resiquimod (R848) (Fig.…”
Section: Chemical Strategies For Modulating the Tmementioning
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