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

Alain T,Lun X,Martineau Y,Sean P,Pulendran B,Petroulakis E,Zemp FJ,Lemay CG,Roy D,Bell JC,Thomas G,Kozma SC,Forsyth PA,Costa-Mattioli M,Sonenberg N

doi

10.1073/pnas.0912344107

subject

Has Abstract

pub_date

2010-01-26 00:00:00

pages

1576-81

issue

4

eissn

0027-8424

issn

1091-6490

pii

0912344107

journal_volume

107

pub_type

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