The lytic activity of VSV-GP treatment dominates the therapeutic effects in a syngeneic model of lung cancer

Schreiber, Liesa-Marie; Urbiola, Carles; Das, Krishna; Spiesschaert, Bart; Kimpel, Janine; Heinemann, Fabian; Stierstorfer, Birgit; Müller, Philipp; Petersson, Monika; Erlmann, Patrik; Laer, Dorotheé von; Wollmann, Guido

doi:10.1038/s41416-019-0574-7

Cited by 27 publications

(35 citation statements)

References 59 publications

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“…41 Hence, we used the B16 IFNAR -/- cells as it was shown that IFNAR deficiency prolongs virus replication. 22 Virus replication in the tumor was confirmed by in vivo bioluminescence imaging (BLI) using a VSV-GP variant expressing the firefly luciferase (VSV-GP-Luc). In comparison to the PBS treated group, i.t.…”

Section: Resultsmentioning

confidence: 99%

Differential infection of murine and human dendritic cell subsets by oncolytic vesicular stomatitis virus variants

et al. 2021

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Oncolytic viruses (OVs) can eradicate tumor cells and elicit antitumor immunity. VSV-GP, a chimeric vesicular stomatitis virus (VSV) with the glycoprotein (GP) of the lymphocytic choriomeningitis virus, is a promising new OV candidate. However, the interaction of VSV-GP with host immune cells is not fully understood. Dendritic cells (DCs) are essential for inducing efficient antitumor immunity. Thus, we aimed to investigate the interaction of VSV-GP with different murine and human DCs subsets in direct comparison to the less cytopathic variant VSV-dM51-GP and wild type VSV. Immature murine bone marrow-derived DCs (BMDCs) were equally infected and killed by VSV and VSV-GP. Human monocyte-derived DCs (moDCs) were more permissive to VSV. Interestingly, VSV-dM51-GP induced maturation instead of killing in both BMDCs and moDCs as well as a pronounced release of pro-inflammatory cytokines. Importantly, matured BMDCs and moDCs were no longer susceptible to VSV-GP infection. Mouse splenic conventional DC type 1 (cDC1) could be infected ex vivo by VSV and VSV-GP to a higher extent than cDC2. Systemic infection of mice with VSV-GP and VSV-dM51-GP resulted in strong activation of cDCs despite low infection rates in spleen and tumor tissue. Human blood cDC1 were equally infected by VSV and VSV-GP, whereas cDC2 showed preferential infection with VSV. Our study demonstrated differential DC infection, activation, and cytokine production after the treatment with VSV and VSV-GP variants among species and subsets, which should be taken into account when investigating immunological mechanisms of oncolytic virotherapy in mouse models and human clinical trials.

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Section: Resultsmentioning

confidence: 99%

Differential infection of murine and human dendritic cell subsets by oncolytic vesicular stomatitis virus variants

et al. 2021

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“…Variants of two of the viruses we used in the preceding experiments, VSV-GFP and Reovirus, are evaluated as potential virotherapy agents in a variety of solid tumors, including lung cancer (Schreiber et al, 2019 38 , Villalona-Calero et al, 2016 39 ). We therefore tested whether inhibition of the AKT/p-IWS1 axis enhances their cytolytic activity against tumor cells.…”

Section: Resultsmentioning

confidence: 99%

“…1, Fig. 2 ), which induces the alternative RNA splicing of U2AF2 (Laliotis et al, 2020 37 ). This shift in the alternative RNA splicing pattern controls the interaction of U2AF65 with yet another splicing factor, Prp19.…”

Section: Discussionmentioning

confidence: 99%

IWS1 phosphorylation by AKT3 controls nuclear export of type I IFN mRNAs and sensitivity to oncolytic viral infection, by regulating the alternative RNA splicing of U2AF2

Laliotis

Kenney

Chavdoula

et al. 2020

Preprint

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Type I IFNs orchestrate the antiviral response. Interestingly, IFNA1 and IFNB1 genes are naturally intronless. Based on previous work, the splicing factor U2 Associated Factor 65 (U2AF65), encoded by U2AF2, and pre-mRNA Processing factor 19 (Prp19) function on the Cytoplasmic Accumulation Region Elements (CAR-E), affecting the nuclear export of intronless genes. We have previously shown that the loss of IWS1 phosphorylation by AKT3, promotes the alternative RNA splicing of U2AF2, resulting in novel transcripts lacking exon 2. This exon encodes part of the Serine-Rich (RS) domain of U2AF65, which is responsible for its binding with Prp19. Here, we show that IWS1 phosphorylation and the U2AF2 RNA splicing pattern affect the nuclear export of introless mRNAs. We also demonstrate that the same axis is required for the proper function of the CAR-Es. Mechanistically, whereas both U2AF65 isoforms bind CAR-E, the recruitment of Prp19 occurs only in cells expressing phosphorylated IWS, promoting intronless genes export. Moreover, analysis of Lung adenocarcinoma patients showed that high p-IWS1 activity correlates with the assembly of the U2AF65/Prp19 complex and export of intronless genes, in vivo. Accordingly, the expression of type I IFNs was decreased in cells deficient in IWS1 phosphorylation and the viral infection was increased. Furthermore, following infection with oncolytic virus, we observed reduced activation of p-STAT1 and expression of Interferon Stimulated Genes (ISG), in cells stimulated by shIWS1-derived supernatant, or cells treated with the pan-AKT inhibitor, MK2206. Consistently, killing curves and apoptosis assays after infection with oncolytic viruses, revealed increased susceptibility upon the loss of IWS1, with subsequent activation of Caspase-mediated death. The treatment of the lung adenocarcinoma cells with MK2206, phenocopied the loss of IWS1 phosphorylation. These data identify a novel mechanism by which the AKT/p-IWS1 axis, by hijacking the epigenetic regulation of RNA splicing and processing, contributes to the resistance to oncolytic viral infection, suggesting that combined inhibition of the splicing machinery and AKT/p-IWS1 signals would sensitize tumors to oncolytic viral treatment.

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“…In this study we focus on replication-competent Vesicular Stomatitis Virus (VSV) vectors, which have been shown to offer great promise as oncolytic agents mainly because (i) they are not pathogenic to humans and (ii) humans do not have pre-existing immunity against these viruses [26,3]. In regard to the interactions between these virus particles and the macrophages, various experimental studies have shown that immune protection against VSV infection is controlled by the induction of a type-I interferon response [53], and therefore, the M1 macrophages are likely to be involved in the elimination of VSV particles. Moreover, it is known that macrophages can be infected by the VSV [50,54].…”

Section: Introductionmentioning

confidence: 99%

A mathematical model for the role of macrophages in the persistence and elimination of oncolytic viruses

Almuallem

Eftimie²

2020

Math Appl Sci Eng

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Replicating oncolytic viruses provide promising treatment strategies against cancer. However, the success of these viral therapies depends mainly on the complex interactions between the virus particles and the host immune cells. Among these immune cells, macrophages represent one of the first line of defence against viral infections. In this paper, we consider a mathematical model that describes the interactions between a commonly-used oncolytic virus, the Vesicular Stomatitis Virus (VSV), and two extreme types of macrophages: the pro-inflammatory M1 cells (which seem to resist infection with VSV) and the anti-inflammatory M2 cells (which can be infected with VSV). We first show the existence of bounded solutions for this differential equations model. Then we investigate the long-term behaviour of the model by focusing on steady states and limit cycles, and study changes in this long-term dynamics as we vary different model parameters. Moreover, through sensitivity analysis we show that the parameters that have the highest impact on the level of virus particles in the system are the viral burst size (from infected macrophages), the virus infection rate, the M1$\to$M2 polarisation rate, and the M1-induced anti-viral immunity.

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The lytic activity of VSV-GP treatment dominates the therapeutic effects in a syngeneic model of lung cancer

Cited by 27 publications

References 59 publications

Differential infection of murine and human dendritic cell subsets by oncolytic vesicular stomatitis virus variants

Differential infection of murine and human dendritic cell subsets by oncolytic vesicular stomatitis virus variants

IWS1 phosphorylation by AKT3 controls nuclear export of type I IFN mRNAs and sensitivity to oncolytic viral infection, by regulating the alternative RNA splicing of U2AF2

A mathematical model for the role of macrophages in the persistence and elimination of oncolytic viruses

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