title: Interferon-β sensitivity of tumor cells correlates with poor response to VA7 virotherapy in mouse glioma models.
abstract: In our recent study, replicative alphaviral vector VA7 was found to be effective against orthotopic human U87-glioma xenografts in an athymic mouse model eradicating the tumors with single intravenous (i.v.) injection. Here, we tested the efficacy of VA7 in immunocompetent orthotopic GL261 and CT-2A glioma models of C57BL/6 mouse in vivo. The cell lines were susceptible to VA7 infection in vitro, but GL261 infection was highly restricted in confluent cell cultures, and mouse interferon-β (IFNβ) pretreatment prevented the replication of VA7 in both cell lines. When mice bearing orthotopic GL261 or CT-2A tumors were administered neurotropic VA7, either i.v. or intracranially (i.c.), the vector was unable to infect the tumor and no survival benefit was achieved. Pretreatments with immunosuppressive cyclophosphamide (CPA) and rapamycin markedly lowered serum-neutralizing antibodies (NAbs) but had no effect on tumor infection or survival. Intracranial GL261 tumors were refractory also in athymic C57BL/6 mice, which have serious defects in their adaptive immunity. Implanted VA7-infected GL261 cells formed tumors with only slightly delayed kinetics and without improving survival thus excluding the participation of physical barriers and indicating robust host IFN action. Mouse and human IFNβ do not seem be species cross-reactive, which might limit the translational relevance of xenograft models in oncolytic virotherapy.
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Janne
authors.initials: J
authors.lastname: Ruotsalainen
authors.forename: Miika
authors.initials: M
authors.lastname: Martikainen
authors.forename: Minna
authors.initials: M
authors.lastname: Niittykoski
authors.forename: Tuulia
authors.initials: T
authors.lastname: Huhtala
authors.forename: Tytti
authors.initials: T
authors.lastname: Aaltonen
authors.forename: Jari
authors.initials: J
authors.lastname: Heikkilä
authors.forename: John
authors.initials: J
authors.lastname: Bell
authors.forename: Markus
authors.initials: M
authors.lastname: Vähä-Koskela
authors.forename: Ari
authors.initials: A
authors.lastname: Hinkkanen
mesh_terms: D000524:Alphavirus / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D016899:Interferon-beta / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D023041:Xenograft Model Antitumor Assays
chemical_list: D016899:Interferon-beta