STING cg16983159 methylation: a key factor for glioblastoma immunosuppression

Qiu, Lei; Yang, Meng; Han, Junhong

doi:10.1038/s41392-022-01093-w

Cited by 5 publications

(7 citation statements)

References 5 publications

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“… 253 – 255 Recent reports also reveal that in GBM, the promoter region of STING is methylated, consistent with the dysfunctional cGAS-STING pathway in glioma cell lines. 212 , 256 , 257 Interestingly, this silencing is not observed in tumor-associated immune cells or the extracellular matrix. 256 Aberrant protein expression in tumors also drives this process.…”

Section: Innate Immune Pathways In Cancermentioning

confidence: 96%

“…However, the TME can induce the suppression of the innate immune pathway through various means, such as by epigenetically inhibiting the expression of key proteins of the innate immune pathway. 256 , 257 For instance, the expression of STING is epigenetically repressed due to methylation at cg16983159 in glioma cells. By applying, decitabine, a DNA methyltransferase inhibitor, STING expression can be restored, thus reinvigorating STING’s responsiveness to its agonist, cGAMP.…”

Section: Cancer Therapeutic Strategies Targeting Innate Immune Pathwaymentioning

confidence: 99%

“…By applying, decitabine, a DNA methyltransferase inhibitor, STING expression can be restored, thus reinvigorating STING’s responsiveness to its agonist, cGAMP. 256 , 257 In a separate study, the combination of zebularine (a demethylating agent) and the STING agonist cGAMP effectively induced ISG expression and augmented the infiltration of CD8 T cells and NK cells into tumors, consequently inhibiting tumor growth and prolonging mouse survival. This combination demonstrated a significantly superior outcome compared to using cGAMP alone.…”

Section: Cancer Therapeutic Strategies Targeting Innate Immune Pathwaymentioning

confidence: 99%

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Harnessing innate immune pathways for therapeutic advancement in cancer

Hu,

Sun,

Lin

et al. 2024

Sig Transduct Target Ther

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The innate immune pathway is receiving increasing attention in cancer therapy. This pathway is ubiquitous across various cell types, not only in innate immune cells but also in adaptive immune cells, tumor cells, and stromal cells. Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment (TME) and improved tumor prognosis in preclinical studies. However, to date, the clinical success of drugs targeting the innate immune pathway remains limited. Interestingly, recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression. The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation. In this review, we observe that the role of the innate immune pathway demonstrates heterogeneity, linked to the tumor development stage, pathway status, and specific cell types. We propose that within the TME, the innate immune pathway exhibits multidimensional diversity. This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks. The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways. Refining our understanding of the tumor’s innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinical application.

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Section: Innate Immune Pathways In Cancermentioning

confidence: 96%

Section: Cancer Therapeutic Strategies Targeting Innate Immune Pathwaymentioning

confidence: 99%

Section: Cancer Therapeutic Strategies Targeting Innate Immune Pathwaymentioning

confidence: 99%

See 1 more Smart Citation

Harnessing innate immune pathways for therapeutic advancement in cancer

Hu,

Sun,

Lin

et al. 2024

Sig Transduct Target Ther

View full text Add to dashboard Cite

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“…These neoantigens can be recognized by adaptive immune cells, leading to immune activation or tolerance, depending on the tolerogenic properties of the TME. Notably, epigenetic regulation of STING (via STING promoter DNA methylation) has been proposed to modulate the immune response in glioma (94). Moreover, STING silencing in glioma can be reversed by DNA methyltransferase inhibition (95).…”

Section: R E V I E W S E R I E S : I M M U N E E N V I R O N M E N T ...mentioning

confidence: 99%

Impact of epigenetic reprogramming on antitumor immune responses in glioma

McClellan¹,

Haase²,

Núñez³

et al. 2023

Journal of Clinical Investigation

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“…The standard care of GBM, surgical resection followed by radiotherapy plus concomitant and maintenance TMZ (RT/TMZ), remains most effective but can only slightly prolong the median survival for 2–3 months [ 3 , 4 ]. While many novel therapies, such as immunotherapy [ 5 – 7 ] and oncolytic virotherapy [ 8 ], have shown great promise in animal studies but not in clinical trials. Complete surgical removal of GBM cells is nearly impossible due to the highly invasive feature of GBM [ 9 , 10 ], and therefore the tumor rapidly relapses; meanwhile, GBM cells evolve during RT/TMZ therapy and can acquire “multidrug resistance” (MDR) [ 2 , 11 ], greatly limiting their efficacy.…”

Section: Introductionmentioning

confidence: 99%

Piperlongumine conquers temozolomide chemoradiotherapy resistance to achieve immune cure in refractory glioblastoma via boosting oxidative stress-inflamation-CD8+-T cell immunity

Liu

Zhou

Jiang

et al. 2023

J Exp Clin Cancer Res

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Background The failure of novel therapies effective in preclinical animal models largely reflects the fact that current models do not really mimic the pathological/therapeutic features of glioblastoma (GBM), in which the most effective temozolomide chemoradiotherapy (RT/TMZ) regimen can only slightly extend survival. How to improve RT/TMZ efficacy remains a major challenge in clinic. Methods Syngeneic G422TN-GBM model mice were subject to RT/TMZ, surgery, piperlongumine (PL), αPD1, glutathione. Metabolomics or transcriptomics data from G422TN-GBM and human GBM were used for gene enrichment analysis and estimation of ROS generation/scavenging balance, oxidative stress damage, inflammation and immune cell infiltration. Overall survival, bioluminescent imaging, immunohistochemistry, and immunofluorescence staining were used to examine therapeutic efficacy and mechanisms of action. Results Here we identified that glutathione metabolism was most significantly altered in metabolomics analysis upon RT/TMZ therapies in a truly refractory and reliable mouse triple-negative GBM (G422TN) preclinical model. Consistently, ROS generators/scavengers were highly dysregulated in both G422TN-tumor and human GBM. The ROS-inducer PL synergized surgery/TMZ, surgery/RT/TMZ or RT/TMZ to achieve long-term survival (LTS) in G422TN-mice, but only one LTS-mouse from RT/TMZ/PL therapy passed the rechallenging phase (immune cure). Furthermore, the immunotherapy of RT/TMZ/PL plus anti-PD-1 antibody (αPD1) doubled LTS (50%) and immune-cured (25%) mice. Glutathione completely abolished PL-synergistic effects. Mechanistically, ROS reduction was associated with RT/TMZ-resistance. PL restored ROS level (mainly via reversing Duox2/Gpx2), activated oxidative stress/inflammation/immune responses signature genes, reduced cancer cell proliferation/invasion, increased apoptosis and CD3+/CD4+/CD8+ T-lymphocytes in G422TN-tumor on the basis of RT/TMZ regimen. Conclusion Our findings demonstrate that PL reverses RT/TMZ-reduced ROS and synergistically resets tumor microenvironment to cure GBM. RT/TMZ/PL or RT/TMZ/PL/αPD1 exacts effective immune cure in refractory GBM, deserving a priority for clinical trials.

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STING cg16983159 methylation: a key factor for glioblastoma immunosuppression

Cited by 5 publications

References 5 publications

Harnessing innate immune pathways for therapeutic advancement in cancer

Harnessing innate immune pathways for therapeutic advancement in cancer

Impact of epigenetic reprogramming on antitumor immune responses in glioma

Piperlongumine conquers temozolomide chemoradiotherapy resistance to achieve immune cure in refractory glioblastoma via boosting oxidative stress-inflamation-CD8+-T cell immunity

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