cGAS/STING axis mediates a topoisomerase II inhibitor–induced tumor immunogenicity

Wang, Zining; Chen, Jiemin; Hu, Jie; Zhang, Hongxia; Xu, Feifei; Wang, He; Wang, Xiaojuan; Li, Mengyun; Lu, Wenhua; Zeng, Gucheng; Zhou, Penghui; Huang, Peng; Chen, Siyu; Li, Wende; Xia, Ling; Xia, Xiaojun

doi:10.1172/jci127471

Cited by 159 publications

(130 citation statements)

References 60 publications

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“…Although cGAS activation is inhibited by nucleosomes, taxol can induce mitotic cell-cycle arrest and sustain divided chromatin in the cytosol to activate the cGAS-STING pathway slowly, and accumulation of signaling could stimulate apoptosis of cancer cells (41). Inhibitors of topoisomerase 1 or 2 used conventionally as chemotherapy drugs trigger minor damage to DNA and accumulation of cytosolic DNA, which can engage cGAS and enhance the anti-tumor or anti-infection responses of cells (255)(256)(257).…”

Section: Targeting the Cgas-sting Pathway For Treatmentmentioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

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Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immunesurveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

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Section: Targeting the Cgas-sting Pathway For Treatmentmentioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

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“…Top1-DNA covalent cleavage complex enables cGAS-mediated cytoplasmic chromatin recognition and immune checkpoint response [ 221 ] ( Figure 5 B). Top2 inhibitors teniposide and doxorubicin potentiate the therapeutic immune checkpoint blockade therapies based on anti-PD-1 (programmed cell death 1) in multiple types of mouse tumor models [ 222 , 223 ]. Besides, ROS produced by Top inhibitors alter the molecular pattern recognized as immunogenic structures and enhance apoptosis [ 224 ] ( Figure 5 B).…”

Section: Future Strategies For Copper Complexes As Top Inhibitors mentioning

confidence: 99%

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

Molinaro

Martoriati

Pélinski

et al. 2020

Cancers

119

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Organometallics, such as copper compounds, are cancer chemotherapeutics used alone or in combination with other drugs. One small group of copper complexes exerts an effective inhibitory action on topoisomerases, which participate in the regulation of DNA topology. Copper complexes inhibitors of topoisomerases 1 and 2 work by different molecular mechanisms, analyzed herein. They allow genesis of DNA breaks after the formation of a ternary complex, or act in a catalytic mode, often display DNA intercalative properties and ROS production, and sometimes display dual effects. These amplified actions have repercussions on the cell cycle checkpoints and death effectors. Copper complexes of topoisomerase inhibitors are analyzed in a broader synthetic view and in the context of cancer cell mutations. Finally, new emerging treatment aspects are depicted to encourage the expansion of this family of highly active anticancer drugs and to expend their use in clinical trials and future cancer therapy.

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“…In keeping with this, a number of groups have demonstrated stimulation of type 1 interferons and cytokines following treatment with DNA damaging agents or ionising radiation in both the in vitro and in vivo settings [4,8,9,20]. Similarly, a recent study screening a panel of FDA-approved drugs for agents that induce immunogenic cell death (ICD), identified the topo-II inhibitor teniposide as a potent ICD inducer [21]. ICD is a mode of cell death reported to enhance release of tumour specific antigens from dying cells and thereby boost immune cell recruitment and T-cell mediated cancer cell death.…”

Section: Discussionmentioning

confidence: 89%

“…ICD is a mode of cell death reported to enhance release of tumour specific antigens from dying cells and thereby boost immune cell recruitment and T-cell mediated cancer cell death. This study also went on to show that in vitro, teniposide activates the cGAS/STING pathway leading to a Type-I interferon response [21]. However, teniposide is a poorly tolerated drug, rarely used in the clinic due to toxicity.…”

Section: Discussionmentioning

confidence: 99%

Topoisomerase II inhibitors induce cGAS-STING dependent inflammation resulting in cytokine induction and immune checkpoint activation

Wilkinson

McCabe

Parkes

et al. 2019

Preprint

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Tumours with genomic instability demonstrate enhanced immunogenicity and potential for response to immune checkpoint blockade (ICB). We previously demonstrated activation of the cGAS-STING pathway following loss of DNA repair, resulting in cytokine induction, lymphocytic infiltration and immune checkpoint activation. Here we explore the role of chemotherapies in inducing this innate immune response, identifying topoisomerase II (topo-II) inhibitors, particularly doxorubicin and epirubicin, as potent inducers of a cGAS-STING dependent interferon response. Mechanistically, topo-II inhibition resulted in significant induction of cytoplasmic DNA and subsequent micronuclei formation, a requirement for efficient cGAS-STING activation and consequent cytokine and immune checkpoint gene induction. Importantly, increased cytokine and immune checkpoint gene expression, as well as increased immune cell infiltration, was also observed in patient derived breast tumour biopsies following topo-II inhibitor-based treatment. Taken together, this study indicates topo-II inhibitors such as doxorubicin, may be best placed to induce immunogenic inflammation, and thereby increase responses to ICB therapies. Running Title: Topoisomerase II inhibitors induce cGAS-STING activation SignificanceThis work demonstrates how topo-II inhibitors induce STING-pathway activation, cytokine induction and immune checkpoint protein upregulation in cancer cells and provides a rationale for combining topo-II inhibitors with ICB therapy in early breast cancer.3

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cGAS/STING axis mediates a topoisomerase II inhibitor–induced tumor immunogenicity

Cited by 159 publications

References 60 publications

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

Topoisomerase II inhibitors induce cGAS-STING dependent inflammation resulting in cytokine induction and immune checkpoint activation

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