title: Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production.
abstract: Oncolytic viruses constitute a promising therapy against malignant gliomas (MGs). However, virus-induced type I IFN greatly limits its clinical application. The kinase mammalian target of rapamycin (mTOR) stimulates type I IFN production via phosphorylation of its effector proteins, 4E-BPs and S6Ks. Here we show that mouse embryonic fibroblasts and mice lacking S6K1 and S6K2 are more susceptible to vesicular stomatitis virus (VSV) infection than their WT counterparts as a result of an impaired type I IFN response. We used this knowledge to employ a pharmacoviral approach to treat MGs. The highly specific inhibitor of mTOR rapamycin, in combination with an IFN-sensitive VSV-mutant strain (VSV(DeltaM51)), dramatically increased the survival of immunocompetent rats bearing MGs. More importantly, VSV(DeltaM51) selectively killed tumor, but not normal cells, in MG-bearing rats treated with rapamycin. These results demonstrate that reducing type I IFNs through inhibition of mTORC1 is an effective strategy to augment the therapeutic activity of VSV(DeltaM51).
authors.affiliation: Department of Biochemistry and Goodman Cancer Center, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Tommy
authors.initials: T
authors.lastname: Alain
authors.forename: XueQing
authors.initials: X
authors.lastname: Lun
authors.forename: Yvan
authors.initials: Y
authors.lastname: Martineau
authors.forename: Polen
authors.initials: P
authors.lastname: Sean
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Petroulakis
authors.forename: Franz J
authors.initials: FJ
authors.lastname: Zemp
authors.forename: Chantal G
authors.initials: CG
authors.lastname: Lemay
authors.forename: Dominic
authors.initials: D
authors.lastname: Roy
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.forename: Sara C
authors.initials: SC
authors.lastname: Kozma
authors.forename: Peter A
authors.initials: PA
authors.lastname: Forsyth
authors.forename: Mauro
authors.initials: M
authors.lastname: Costa-Mattioli
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000628:therapy* / Q000821:virology; D007370:Interferon Type I / Q000096:biosynthesis*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy; D011506:Proteins; D051381:Rats; D011916:Rats, Inbred F344; D019893:Ribosomal Protein S6 Kinases / Q000172:deficiency / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000172:deficiency / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism*; D054243:Vesicular Stomatitis / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D018116:Vesiculovirus / Q000235:genetics / Q000502:physiology*
chemical_list: D007370:Interferon Type I; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus