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PML has a predictive role in tumor cell permissiveness to interferon-sensitive oncolytic viruses

Gene Therapy volume 16, pages 1077–1087 (2009)Cite this article

Abstract

The oncotropic phenotypes of several viruses correlate with tumor-associated deficiencies within interferon (IFN) signaling pathways. This observation formed the conceptual basis for developing oncolytic viruses deleted for viral proteins that inhibit the host IFN-dependent antiviral response, such as herpes simplex virus type-1 infected cell protein-0 (ICP0) and vesicular stomatitis virus matrix protein. Many viruses have evolved means to disrupt promyelocytic leukemia protein (PML) nuclear bodies. For example, ICP0 promotes PML degradation to inhibit the antiviral activities of this IFN-stimulated gene. As PML is downregulated in a variety of tumors, we hypothesized ICP0-null herpes simplex type-1 viruses are selectively oncolytic in tumors with impaired PML expression. We illustrate that ICP0-null herpes simplex type-1 viruses target tumor cells that either possess impaired PML signaling or cannot upregulate PML because of impaired IFN responsiveness. Disruption of PML signaling through overexpression of the dominant-negative protein PML-retinoic acid receptor alpha in PML-positive cells renders them sensitive to oncolysis by ICP0-null herpes simplex virus type-1 and vesicular stomatitis virus M protein mutant viruses, whereas PML overexpression reverses this phenomenon. Together, these data illustrate that PML mediates an antiviral mechanism that predicts the tropism of IFN-sensitive oncolytic viruses. To our knowledge, these viruses are the first examples of anti-cancer therapeutics capable of targeting deficiencies in PML expression.

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Acknowledgements

We thank Brian Lichty (McMaster University, Hamilton, Ontario, Canada), Samuel Rabkin (Harvard University, Boston, MA, USA), Suzanne Kamel-Reid (University of Toronto, Toronto, Ontario, Canada), Richard Wells (University of Toronto, Toronto, Ontario, Canada), Malayannan Subramaniam (Mayo Clinic College of Medicine, Rochester, MN, USA) and Kun-Sang Chang (University of Texas, Houston, TX, USA) for plasmids, viruses and cell lines, and Derek Cummings (McMaster University, Hamilton, Ontario, Canada) for technical assistance. Preliminary studies were sponsored by the US Army Medical Research and Materiel Command Exploration—Hypothesis Development Award. Subsequent studies were funded by the Canadian Breast Cancer Foundation and the Ontario Institute for Cancer Research. KLM holds an Rx&D Health Sciences Career Award and PTS and RMR hold Ontario Graduate Scholarships.

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Authors and Affiliations

  1. Departments of Biochemistry and Biomedical Sciences, McMaster University, Ontario, Hamilton, Canada

    P T Sobol, R M Rodrigues & K L Mossman

  2. Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, McMaster University, Ontario, Hamilton, Canada

    J L Hummel & K L Mossman

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  1. P T Sobol
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Correspondence to K L Mossman.

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Sobol, P., Hummel, J., Rodrigues, R. et al. PML has a predictive role in tumor cell permissiveness to interferon-sensitive oncolytic viruses. Gene Ther 16, 1077–1087 (2009). https://doi.org/10.1038/gt.2009.68

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