title: Clonal variation in interferon response determines the outcome of oncolytic virotherapy in mouse CT26 colon carcinoma model.
abstract: In our earlier studies, Semliki Forest virus vector VA7 completely eliminated type I interferon (IFN-I)-unresponsive human U87-luc glioma xenografts, whereas interferon-responsive mouse gliomas proved refractory. Here, we describe in two clones of CT26 murine colon carcinoma, opposed patterns of IFN-I responsiveness and sensitivity to VA7. Both CT26WT and CT26LacZ clones secreted biologically active interferon in vitro upon virus infection but only CT26WT cells were protected. Focal infection of CT26WT cultures was self-limiting but could be rescued using IFN-I pathway inhibitor Ruxolitinib or antibody against IFNβ. Whole transcriptome sequencing (RNA-Seq) and protein expression analysis revealed that CT26WT cells constitutively expressed 56 different genes associated with pattern recognition and IFN-I signaling pathways, spanning two reported anti-RNA virus gene signatures and 22 genes with reported anti-alphaviral activity. Whereas CT26WT tumors were strictly virus-resistant in vivo, infection of CT26LacZ tumors resulted in complete tumor eradication in both immunocompetent and severe combined immune deficient mice. In double-flank transplantation experiments, CT26WT tumors grew despite successful eradication of CT26LacZ tumors from the contralateral flank. Tumor growth progressed uninhibited also when CT26LacZ inoculums contained only a small fraction of CT26WT cells, demonstrating dominance of IFN responsiveness when heterogeneous tumors are targeted with interferon-sensitive oncolytic viruses.
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: J J
authors.initials: JJ
authors.lastname: Ruotsalainen
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: M U
authors.initials: MU
authors.lastname: Kaikkonen
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Niittykoski
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: M W
authors.initials: MW
authors.lastname: Martikainen
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: C G
authors.initials: CG
authors.lastname: Lemay
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Cox
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: N S
authors.initials: NS
authors.lastname: De Silva
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Kus
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: T J
authors.initials: TJ
authors.lastname: Falls
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: J-S
authors.initials: JS
authors.lastname: Diallo
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Le Boeuf
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: J C
authors.initials: JC
authors.lastname: Bell
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: A E
authors.initials: AE
authors.lastname: Hinkkanen
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: M J
authors.initials: MJ
authors.lastname: Vähä-Koskela
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D024201:Bystander Effect; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D007370:Interferon Type I / Q000494:pharmacology / Q000627:therapeutic use; D016899:Interferon-beta / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009336:Necrosis; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D012672:Semliki forest virus / Q000235:genetics*; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007370:Interferon Type I; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D016899:Interferon-beta