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Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production

Tommy Alain1, XueQing Lun, Yvan Martineau

  • 1Department of Biochemistry and Goodman Cancer Center, McGill University, Montreal, QC H3G 1Y6, Canada.

Proceedings of the National Academy of Sciences of the United States of America
|January 19, 2010
PubMed

Insights

Inhibiting mTOR with rapamycin enhances oncolytic virus therapy for malignant gliomas. This approach boosts vesicular stomatitis virus (VSV) effectiveness against tumors while sparing healthy cells.

Area of Science:

  • Oncolytic virotherapy
  • Cancer immunology
  • Molecular targeted therapy

Background:

  • Oncolytic viruses show promise for malignant gliomas (MGs) but are limited by type I interferon (IFN) responses.
  • Mammalian target of rapamycin (mTOR) kinase pathway regulates type I IFN production, impacting viral efficacy.

Purpose of the Study:

  • To investigate the role of S6 kinases (S6K) in type I IFN response to vesicular stomatitis virus (VSV).
  • To evaluate the combined efficacy of mTOR inhibition and an engineered VSV mutant for treating MGs.

Main Methods:

  • Assessed VSV susceptibility in S6K1/S6K2 deficient cells and mice.
  • Administered rapamycin (mTOR inhibitor) and VSV(DeltaM51) (IFN-sensitive mutant) to rats with MGs.

Main Results:

  • S6K1/S6K2 deficiency led to impaired type I IFN response and increased VSV susceptibility.
  • Combined rapamycin and VSV(DeltaM51) treatment significantly improved survival in MGs-bearing rats.
  • VSV(DeltaM51) demonstrated selective tumor cell killing in rapamycin-treated rats.

Conclusions:

  • Inhibition of mTORC1 reduces type I IFNs, enhancing oncolytic VSV efficacy.
  • Pharmacoviral therapy combining mTOR inhibition with VSV(DeltaM51) is a promising strategy for malignant gliomas.

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