title: Innate immune defense defines susceptibility of sarcoma cells to measles vaccine virus-based oncolysis.
abstract: The oncolytic potential of measles vaccine virus (MeV) has been demonstrated in several tumor entities. Here, we investigated the susceptibility of eight sarcoma cell lines to MeV-mediated oncolysis and found five to be susceptible, whereas three proved to be resistant. In the MeV-resistant cell lines, we often observed an inhibition of viral replication along with a strong upregulation of the intracellular virus-sensing molecule RIG-I and of the interferon (IFN)-stimulated gene IFIT1. Not only expression of IFIT1 but also phosphorylation of IFN-stimulated Stat1 took place rapidly and were found to be persistent over time. In contrast, susceptible cell lines showed a much weaker, delayed, or completely missing expression of IFIT1 as well as a delayed or only transient phosphorylation of Stat1, whereas exogenic stimulation with beta interferon (IFN-β) resulted in a comparable profound activation of Stat1 and expression of IFIT1 in all cell lines. Pretreatment with IFN-β rendered three of the susceptible cell lines more resistant to MeV-mediated oncolysis. These data suggest that differences in the innate immune defense often account for different degrees of susceptibility of sarcoma cell lines to MeV-mediated oncolysis. From a therapeutic perspective, we were able to overcome resistance to MeV by increasing the multiplicity of infection (MOI) and by addition of the prodrug 5-fluorocytosine (FC), thereby exploiting the suicide gene function of virotherapeutic vector MeV-SCD armed with the SCD fusion protein, which consists of yeast cytosine deaminase and yeast uracil phosphoribosyltransferase.
authors.affiliation: Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Berchtold
authors.forename: Johanna
authors.initials: J
authors.lastname: Lampe
authors.forename: Timo
authors.initials: T
authors.lastname: Weiland
authors.forename: Irina
authors.initials: I
authors.lastname: Smirnow
authors.forename: Sabine
authors.initials: S
authors.lastname: Schleicher
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Kopp
authors.forename: Jeanette
authors.initials: J
authors.lastname: Reiser
authors.forename: Frank
authors.initials: F
authors.lastname: Stubenrauch
authors.forename: Nora
authors.initials: N
authors.lastname: Mayer
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
authors.forename: Michael
authors.initials: M
authors.lastname: Bitzer
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Lauer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D016899:Interferon-beta / Q000276:immunology; D008459:Measles virus / Q000254:growth & development* / Q000276:immunology* / Q000502:physiology; D050504:Oncolytic Viruses / Q000254:growth & development* / Q000276:immunology* / Q000502:physiology; D016601:RNA-Binding Proteins; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C484290:IFIT1 protein, human; D016601:RNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D016899:Interferon-beta