How cancer cells make and respond to interferon-I

Cheon, HyeonJoo; Wang, Yuxin; Wightman, Samantha M.; Jackson, Mark W.; Stark, George R.

doi:10.1016/j.trecan.2022.09.003

Cited by 77 publications

(58 citation statements)

References 63 publications

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“…Because of the essential function of HDACs in modulating immune responses, the influence of HDACi on the regulation of type I IFNs has already been addressed in several studies, showing downregulation in some studies and upregulation in others (Salvi et al 2010;Yang et al 2022;Li et al 2016). The latter may be explained by the fact that the expression of IFNs in cancer cells can be either constitutive or inducible, depending on the cell type and the specific molecular mechanisms involved (Cheon et al 2023). We have previously shown the expression of IFNs in MCC cell lines on mRNA level and now confirmed it on protein level by intracellular cytokine staining (Paulson et al 2011).…”

Section: Discussionmentioning

confidence: 99%

“…All the experiments were repeated at least twice ◂ activation (Cenciarelli et al 2017). Normal cells express infrequent and low levels of ISGs, whereas interferon produced by cells in the tumor microenvironment, as well as by the tumor cells themselves, induces their expression (Cheon et al 2023). The induced ISG profile may ultimately dictate the cellular response to IFNα signaling mediated by HES1 suppression in WaGa cells.…”

Section: Discussionmentioning

confidence: 99%

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The HDAC inhibitor domatinostat induces type I interferon α in Merkel cell carcinoma by HES1 repression

Srinivas

Song

Lei

et al. 2023

J Cancer Res Clin Oncol

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Background Class I selective histone deacetylase inhibitors (HDACi) have been previously demonstrated to not only increase major histocompatibility complex class I surface expression in Merkel cell carcinoma (MCC) cells by restoring the antigen processing and presentation machinery, but also exert anti-tumoral effect by inducing apoptosis. Both phenomena could be due to induction of type I interferons (IFN), as has been described for HDACi. However, the mechanism of IFN induction under HDACi is not fully understood because the expression of IFNs is regulated by both activating and inhibitory signaling pathways. Our own preliminary observations suggest that this may be caused by suppression of HES1. Methods The effect of the class I selective HDACi domatinostat and IFNα on cell viability and the apoptosis of MCPyV-positive (WaGa, MKL-1) and -negative (UM-MCC 34) MCC cell lines, as well as, primary fibroblasts were assessed by colorimetric methods or measuring mitochondrial membrane potential and intracellular caspase-3/7, respectively. Next, the impact of domatinostat on IFNA and HES1 mRNA expression was measured by RT-qPCR; intracellular IFNα production was detected by flow cytometry. To confirm that the expression of IFNα induced by HDACi was due to the suppression of HES1, it was silenced by RNA interference and then mRNA expression of IFNA and IFN-stimulated genes was assessed. Results Our studies show that the previously reported reduction in viability of MCC cell lines after inhibition of HDAC by domatinostat is accompanied by an increase in IFNα expression, both of mRNA and at the protein level. We confirmed that treatment of MCC cells with external IFNα inhibited their proliferation and induced apoptosis. Re-analysis of existing single-cell RNA sequencing data indicated that induction of IFNα by domatinostat occurs through repression of HES1, a transcriptional inhibitor of IFNA; this was confirmed by RT-qPCR. Finally, siRNA-mediated silencing of HES1 in the MCC cell line WaGa not only increased mRNA expression of IFNA and IFN-stimulated genes but also decreased cell viability. Conclusion Our results demonstrate that the direct anti-tumor effect of HDACi domatinostat on MCC cells is at least in part mediated via decreased HES1 expression allowing the induction of IFNα, which in turn causes apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The HDAC inhibitor domatinostat induces type I interferon α in Merkel cell carcinoma by HES1 repression

Srinivas

Song

Lei

et al. 2023

J Cancer Res Clin Oncol

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“…Of note, in the context of inflammation, the core necroptosis pathway machinery has been described to be regulated as part of a transcriptional IFN response including RIPK3 52 , ZBP1 53,54 and MLKL 55 . While the KRAS-induced soluble type I IFN response may overall serve prosurvival responses and resistance to DNA damage 56 it comes at the cost of high necroptotic priming. In addition, we find that KRAS-induced type I IFN production is STING-dependent, yet how activated KRAS might activate STING remains to be discovered.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic KRAS-induces necroptotic priming of pancreatic neoplasia

Tishina,

Dahlhaus,

Androulidaki

et al. 2023

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality. PDAC expresses high levels of caspase 8, a central enzyme controlling various types of regulated cell death. Here, using genetically engineered mouse models we find that oncogenic KRAS-driven neoplastic transformation induces a transcriptional state of necroptotic priming, but necroptosis itself is counter selected against through co-upregulation of caspase 8. Mechanistically, expression of the driver oncogene KRAS induced a STING-dependent type I interferon (IFN) response resulting in upregulation of the necroptosis pathway leading to necroptotic priming. High caspase 8 expression in precursor lesions was a result of co-selection to prevent necroptosis. Hence, genetic or pharmacological targeting of caspase 8 was therapeutically highly efficacious in models of genetically engineered PDAC in vivo. These results identify type I IFN-induced necroptotic priming as synthetic lethality of KRAS-driven PDAC and show that targeting it has therapeutic benefit in this incurable malignancy.

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“…ENPP1 promoted neutrophil extracellular trap (NET) formation via tumor cell expression of haptoglobin, supporting relapse and protecting the tumor from radiotherapy (Ruiz-Fernandez de Cordoba et al, 2022). Additionally, both expression of interferons and STING activation are associated with differentiation of the tumor, reduced stem cell capacity and reduced expression of epithelialmesenchymal transition (EMT) gene signature (Cheng et al, 2020;Cheon et al, 2022;Goswami et al, 2022). Targeting ENPP1 reduced expression of EMT markers and signatures (Goswami et al, 2022).…”

Section: Induction Of Ifn Expression Through Sustaining Sting Activationmentioning

confidence: 99%

Tailoring therapies to counter the divergent immune landscapes of breast cancer

Attalla

Taifour²,

Muller³

2023

Front. Cell Dev. Biol.

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Breast cancer remains a significant clinical concern affecting millions of women worldwide. Immunotherapy is a rapidly growing drug class that has revolutionized cancer treatment but remains marginally successful in breast cancer. The success of immunotherapy is dependent on the baseline immune responses as well as removing the brakes off pre-existing anti-tumor immunity. In this review, we summarize the different types of immune microenvironment observed in breast cancer as well as provide approaches to target these different immune subtypes. Such approaches have demonstrated pre-clinical success and are currently under clinical evaluation. The impact of combination of these approaches with already approved chemotherapies and immunotherapies may improve patient outcome and survival.

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How cancer cells make and respond to interferon-I

Cited by 77 publications

References 63 publications

The HDAC inhibitor domatinostat induces type I interferon α in Merkel cell carcinoma by HES1 repression

The HDAC inhibitor domatinostat induces type I interferon α in Merkel cell carcinoma by HES1 repression

Oncogenic KRAS-induces necroptotic priming of pancreatic neoplasia

Tailoring therapies to counter the divergent immune landscapes of breast cancer

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