期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 4, 页码 1576-1581出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0912344107
关键词
innate antiviral immunity; malignant gliomas; mTORC1; oncolytic viruses
资金
- National Cancer Institute of Canada
- Canadian Cancer Society
- Canadian Institutes of Health Research
- Alberta Heritage Foundation for Medical Research
- Cancer Care Foundation of Alberta
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 Delta M51), dramatically increased the survival of immunocompetent rats bearing MGs. More importantly, VSV Delta M51 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 Delta M51.
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