Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production.
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).
Alain
Tommy
T
Department of Biochemistry and Goodman Cancer Center, McGill University, Montreal, QC H3G 1Y6, Canada.
Lun
XueQing
X
Martineau
Yvan
Y
Sean
Polen
P
Pulendran
Bali
B
Petroulakis
Emmanuel
E
Zemp
Franz J
FJ
Lemay
Chantal G
CG
Roy
Dominic
D
Bell
John C
JC
Thomas
George
G
Kozma
Sara C
SC
Forsyth
Peter A
PA
Costa-Mattioli
Mauro
M
Sonenberg
Nahum
N
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*
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