Modulation of the Type I Interferon Response Defines the Sensitivity of Human Melanoma Cells to Oncolytic Measles Virus

Allagui, Ferdaous; Achard, Catherine; Panterne, Clarisse; Combredet, Chantal; Labarrière, Nathalie; Dréno, Brigitte; Elgaaïed, Amel Benammar; Pouliquen, Daniel; Tangy, Frédéric; Fonteneau, Jean-François; Grégoire, Marc; Boisgerault, Nicolas

doi:10.2174/1566523217666170102110502

Cited by 26 publications

(11 citation statements)

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“…We further tested whether a number of inhibitors affecting antiviral responses and oncolytic virus replication might rescue G207 replication in GSCs. We treated GSCs with C16 (PKR inhibitor) (34), ruxolitinib (JAK1/2 inhibitor) (35,36), and sunitinib (multikinase inhibitor) (37,38). None of these inhibitors rescued G207 replication or affected replication of FΔ6 in GSCs (Fig.…”

Section: Figmentioning

confidence: 99%

Restriction of Replication of Oncolytic Herpes Simplex Virus with a Deletion of γ34.5 in Glioblastoma Stem-Like Cells

Peters

Paget

Tshilenge

et al. 2018

J Virol

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Oncolytic viruses, including herpes simplex viruses (HSVs), are a new class of cancer therapeutic engineered to infect and kill cancer cells, while sparing normal tissue. To ensure that oncolytic HSV (oHSV) is safe in the brain, all oHSVs in clinical trial for glioma lack the γ34.5 genes responsible for neurovirulence. However, loss of γ34.5 attenuates growth in cancer cells. Glioblastoma (GBM) is a lethal brain tumor that is heterogeneous and contains a subpopulation of cancer stem cells, termed GBM stem-like cells (GSCs), that likely promote tumor progression and recurrence. GSCs and matched serum-cultured GBM cells (ScGCs), representative of bulk or differentiated tumor cells, were isolated from the same patient tumor specimens. ScGCs are permissive to γ34.5-deleted oHSV replication and cell killing, while patient-matched GSCs were not, implying an underlying biological difference between stem and bulk cancer cells. GSCs specifically restrict the synthesis of HSV1 true late (TL) proteins, without affecting viral DNA replication or transcription of TL genes. A global shutoff of cellular protein synthesis also occurs late after γ34.5-deleted oHSV infection of GSCs, but does not affect the synthesis of early and leaky late viral proteins. Levels of phosphorylated eIF2α and eIF4E do not correlate with cell permissivity. Expression of Us11 in GSCs rescues replication of γ34.5-deleted oHSV. The difference in permissivity between GSCs and ScGCs to γ34.5-deleted oHSV illustrates a selective translational regulatory pathway in GSCs that may be operative in other stem-like cells and has implications for creating oHSVs. Herpes simplex virus (HSV) can be genetically engineered to endow cancer selective replication and oncolytic activity. γ34.5, a key neurovirulence gene, has been deleted in all oncolytic HSVs in clinical trial for glioma. Glioblastoma stem-like cells (GSCs) are a subpopulation of tumor cells thought to drive tumor heterogeneity and therapeutic resistance. GSCs are non-permissive for γ34.5-deleted HSV, while non-stem-like cancer cells from the same patient tumors are permissive. GSCs restrict true late protein synthesis, despite normal viral DNA replication and transcription of all kinetic classes. This is specific for true late translation, as early and leaky late transcripts are translated late in infection, notwithstanding shutoff of cellular protein synthesis. Expression of Us11 in GSCs rescues the replication of γ34.5-deleted HSV. We have identified a cell type specific innate response to HSV1 that limits oncolytic activity in glioblastoma.

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Section: Figmentioning

confidence: 99%

Restriction of Replication of Oncolytic Herpes Simplex Virus with a Deletion of γ34.5 in Glioblastoma Stem-Like Cells

Peters

Paget

Tshilenge

et al. 2018

J Virol

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“…Whole viruses are also under investigation as new approaches to treating cancer, a field referred to as viral oncolytics, in which viruses selectively target and kill cancer cells as well as enhancing natural immune cell killing of cancer cells [5,6]. Adenoviruses, herpesviruses, measles, senecavirus and poxviruses, such as vaccinia and myxoma, are all in active development as treatments for many cancers, including multiple myeloma, melanoma, sarcomas and brain cancers such as glioblastoma multiforma (GBM) [7][8][9][10][11]. The rabbit-derived myxomavirus is one such virus now demonstrated to selectively target, infect and kill cancer cells, without infecting or killing normal, noncancerous mammalian and human cells [6].…”

Section: Introductionmentioning

confidence: 99%

Deriving Immune Modulating Drugs from Viruses—A New Class of Biologics

Yaron

Zhang

Guo

et al. 2020

JCM

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Viruses are widely used as a platform for the production of therapeutics. Vaccines containing live, dead and components of viruses, gene therapy vectors and oncolytic viruses are key examples of clinically-approved therapeutic uses for viruses. Despite this, the use of virus-derived proteins as natural sources for immune modulators remains in the early stages of development. Viruses have evolved complex, highly effective approaches for immune evasion. Originally developed for protection against host immune responses, viral immune-modulating proteins are extraordinarily potent, often functioning at picomolar concentrations. These complex viral intracellular parasites have “performed the R&D”, developing highly effective immune evasive strategies over millions of years. These proteins provide a new and natural source for immune-modulating therapeutics, similar in many ways to penicillin being developed from mold or streptokinase from bacteria. Virus-derived serine proteinase inhibitors (serpins), chemokine modulating proteins, complement control, inflammasome inhibition, growth factors (e.g., viral vascular endothelial growth factor) and cytokine mimics (e.g., viral interleukin 10) and/or inhibitors (e.g., tumor necrosis factor) have now been identified that target central immunological response pathways. We review here current development of virus-derived immune-modulating biologics with efficacy demonstrated in pre-clinical or clinical studies, focusing on pox and herpesviruses-derived immune-modulating therapeutics.

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“…There is now evidence that the anti-viral state of the cells likely plays an important role in susceptibility to MV [29]. Indeed, the presence of an intact type I interferon-response pathway in patient tumor samples was shown to correlate strongly with the suppression of MV replication in these cells: the IFN I gene expression level, indicating that the healthy cells and primary tumor cells resistant to virus-mediated oncolysis retained functional antiviral type-I IFN pathways impaired replication of MV, while sensitive cells were defective in these pathways [30,31]. However, other authors reported that melanoma cells retained the ability to release IFN in response to MV infection and were not detrimental to viral killing [10].…”

Section: Discussionmentioning

confidence: 99%

The Susceptibility of Human Melanoma Cells to Infection with the Leningrad-16 Vaccine Strain of Measles Virus

Ammour

Ryabaya

Shchetinina

et al. 2020

Viruses

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Oncolytic viruses, including live attenuated measles virus (MV) vaccine strains, have recently been shown as promising therapeutic agents against human malignancies. In this study, the oncolytic potential of the attenuated vaccine strain Leningrad-16 (L-16) of MV was evaluated in a panel of human metastatic melanoma cell lines. The L-16 measles virus was shown to replicate within melanoma cells mediating direct cell killing of tumor cells, although all melanoma cell lines varied in regard to their ability to respond to L-16 MV infection, as revealed by the different pattern of the Interferon Stimulated Gene expression, cytokine release and mechanisms of cell death. Furthermore, the statistically significant L-16 measles virus related tumor growth inhibition was demonstrated in a melanoma xenograft model. Therefore, L-16 MV represents an appealing oncolytic platform for target delivery of therapeutic genes along with other attenuated measles virus strains.

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Modulation of the Type I Interferon Response Defines the Sensitivity of Human Melanoma Cells to Oncolytic Measles Virus

Abstract: Type I interferon response is the main determinant for the sensitivity or resistance of melanoma to oncolytic MV infection. This will have to be taken into account for future clinical trials on oncolytic MV.

Cited by 26 publications

References 0 publications

Restriction of Replication of Oncolytic Herpes Simplex Virus with a Deletion of γ34.5 in Glioblastoma Stem-Like Cells

Restriction of Replication of Oncolytic Herpes Simplex Virus with a Deletion of γ34.5 in Glioblastoma Stem-Like Cells

Deriving Immune Modulating Drugs from Viruses—A New Class of Biologics

The Susceptibility of Human Melanoma Cells to Infection with the Leningrad-16 Vaccine Strain of Measles Virus

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