ATR inhibition potentiates ionizing radiation‐induced interferon response via cytosolic nucleic acid‐sensing pathways

Feng, Xu; Tubbs, Anthony; Zhang, Chunchao; Tang, Mengfan; Sridharan, Sriram; Wang, Chao; Jiang, Dadi; Su, Dan; Zhang, Huimin; Chen, Zhe; Nie, Litong; Xiong, Yun; Huang, Min; Nussenzweig, André; Chen, Junjie

doi:10.15252/embj.2019104036

Cited by 104 publications

(111 citation statements)

References 46 publications

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“…Following treatment with IR, cytoplasmic small non-coding RNAs (sncRNAs) activated retinoic acid-inducible gene I (RIG-I; a cytosolic RNA sensor upstream of MAVS), initiating MAVS-mediated induction of type I IFNs [ 96 ]. Feng et al (2020) demonstrated that MAVS and STING are both important for type I IFN production following IR, but the precise contribution of each pathway is dependent on the cell line being examined [ 97 ]. The authors propose that AT-rich dsDNA fragments released post-irradiation may be transcribed by RNA polymerase III at varying efficiencies depending on the cell line, providing the cytosolic RNA-ligand necessary to stimulate MAVS-regulated type I IFN production [ 97 ].…”

Section: Sting-independent Activation Of Type I Interferons Followmentioning

confidence: 99%

“…Feng et al (2020) demonstrated that MAVS and STING are both important for type I IFN production following IR, but the precise contribution of each pathway is dependent on the cell line being examined [ 97 ]. The authors propose that AT-rich dsDNA fragments released post-irradiation may be transcribed by RNA polymerase III at varying efficiencies depending on the cell line, providing the cytosolic RNA-ligand necessary to stimulate MAVS-regulated type I IFN production [ 97 ]. Previous studies are consistent with this notion, having shown that AT-rich dsDNA serves as a template for RNA polymerase III synthesis of dsRNA, which then activates RIG-I and subsequent MAVS-mediated production of type I IFNs [ 98 , 99 ].…”

Section: Sting-independent Activation Of Type I Interferons Followmentioning

confidence: 99%

“…Hafnium oxide nanoparticles (i.e., NBTXR3) in combination with IR enhanced DNA damage in a colorectal cancer cell line leading to increased activation of the cGAS–STING pathway [ 122 ]. ATR inhibition potentiated type I IFN production in concert with IR in a cGAS–STING-dependent manner [ 97 ]. Moreover, ATR inhibition in combination with IR and immune checkpoint blockade resulted in superior antitumor efficacy in hepatocellular carcinoma models in a cGAS–STING-mediated manner [ 123 ].…”

Section: Augmenting Sting Signaling To Enhance Radiation-induced Amentioning

confidence: 99%

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The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

Storozynsky

Hitt

2020

IJMS

136

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Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS–STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS–STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer—highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS–STING signaling, deleterious effects associated with cGAS–STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS–STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes.

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Section: Sting-independent Activation Of Type I Interferons Followmentioning

confidence: 99%

Section: Sting-independent Activation Of Type I Interferons Followmentioning

confidence: 99%

Section: Augmenting Sting Signaling To Enhance Radiation-induced Amentioning

confidence: 99%

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The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

Storozynsky

Hitt

2020

IJMS

136

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“…The association of TIB with RR may be related to the dysfunction of immunoglobulin generated process by B cells. In contrast, the biological function of the RS module was closely related to the type I interferon pathway, which has been reported to play an important role in the immune response of RT (Burnette et al, 2011;Feng et al, 2020). Therefore, further studies on the roles of hub genes in RR and RS modules are needed.…”

Section: Discussionmentioning

confidence: 94%

Identification of Radiotherapy-Associated Genes in Lung Adenocarcinoma by an Integrated Bioinformatics Analysis Approach

Wang

Han

Liu

et al. 2021

Front. Mol. Biosci.

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Radiotherapy (RT) plays an important role in the prognosis of lung adenocarcinoma (LUAD) patients, but the radioresistance (RR) of LUAD is still a challenge that needs to be overcome. The current study aimed to investigate LUAD patients with RR to illuminate the underlying mechanisms. We utilized gene set variation analysis (GSVA) and The Cancer Immunome Atlas (TCIA) database to characterize the differences in biological functions and neoantigen-coding genes between RR and radiosensitive (RS) patients. Weighted Gene co-expression network analysis (WGCNA) was used to explore the relationship between RT-related traits and hub genes in two modules, i.e., RR and RS; two representative hub genes for RR (MZB1 and DERL3) and two for RS (IFI35 and PSMD3) were found to be related to different RT-related traits. Further analysis of the hub genes with the Lung Cancer Explorer (LCE), PanglaoDB and GSVA resources revealed the differences in gene expression levels, cell types and potential functions. On this basis, the Tumor and Immune System Interaction Database (TISIDB) was used to identify the potential association between RR genes and B cell infiltration. Finally, we used the Computational Analysis of Resistance (CARE) database to identify specific gene-associated drugs for RR patients and found that GSK525762A and nilotinib might be promising candidates for RR treatment. Taken together, these results demonstrate that B cells in TME may have a significant impact on the RT and that these two drug candidates, GSK525762A and nilotinib, might be helpful for the treatment of RR patients.

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“…A few examples of this have been recently reported: STING, downstream of dsDNA-activated cGAS, can also be stimulated by the RNA-sensing RLRs [ 74 ]. Immunostimulatory dsDNA can be transcribed into dsRNA, and recognized by MAVS [ 75 ] ( Figure 1 G). Another PRR, ZBP1, recognizes both dsDNA and dsRNA in their left-handed Z-form [ 76 , 77 ].…”

Section: Other Sources Of Immunostimulatory Nucleic Acidsmentioning

confidence: 99%

Alerting the immune system to DNA damage: micronuclei as mediators

MacDonald

Benguerfi

Harding

2020

Essays in Biochemistry

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Healthy cells experience thousands of DNA lesions per day during normal cellular metabolism, and ionizing radiation and chemotherapeutic drugs rely on DNA damage to kill cancer cells. In response to such lesions, the DNA damage response (DDR) activates cell-cycle checkpoints, initiates DNA repair mechanisms, or promotes the clearance of irreparable cells. Work over the past decade has revealed broader influences of the DDR, involving inflammatory gene expression following unresolved DNA damage, and immune surveillance of damaged or mutated cells. Subcellular structures called micronuclei, containing broken fragments of DNA or whole chromosomes that have been isolated away from the rest of the genome, are now recognized as one mediator of DDR-associated immune recognition. Micronuclei can initiate pro-inflammatory signaling cascades, or massively degrade to invoke distinct forms of genomic instability. In this mini-review, we aim to provide an overview of the current evidence linking the DDR to activation of the immune response through micronuclei formation, identifying key areas of interest, open questions, and emerging implications.

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ATR inhibition potentiates ionizing radiation‐induced interferon response via cytosolic nucleic acid‐sensing pathways

Cited by 104 publications

References 46 publications

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

Identification of Radiotherapy-Associated Genes in Lung Adenocarcinoma by an Integrated Bioinformatics Analysis Approach

Alerting the immune system to DNA damage: micronuclei as mediators

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