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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
12:42

Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo

Published on: January 7, 2019

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

P T Sobol1, J L Hummel, R M Rodrigues

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

Gene Therapy
|May 29, 2009
PubMed

Insights

Oncolytic viruses lacking ICP0 target tumors with low PML expression by exploiting interferon pathway deficiencies. These viruses represent novel anti-cancer therapeutics for specific tumor types.

Area of Science:

  • Virology
  • Oncology
  • Immunology

Background:

  • Oncolytic viruses are engineered to target cancer cells, often by exploiting tumor-specific defects.
  • Viral proteins can inhibit host antiviral responses, including interferon (IFN) signaling pathways.
  • Promyelocytic leukemia (PML) nuclear bodies are disrupted by many viruses and play a role in antiviral defense.

Purpose of the Study:

  • To investigate the hypothesis that ICP0-null herpes simplex type-1 viruses are selectively oncolytic in tumors with impaired PML expression.
  • To determine if PML downregulation predicts sensitivity to oncolytic viruses with impaired IFN antagonism.
  • To explore PML's role as a predictor of oncolytic virus tropism.

Main Methods:

  • Utilized ICP0-null herpes simplex type-1 viruses and vesicular stomatitis virus M protein mutant viruses.
  • Assessed viral oncolysis in tumor cells with varying PML expression levels and IFN responsiveness.
  • Investigated the effect of disrupting PML signaling via dominant-negative PML-retinoic acid receptor alpha.

Main Results:

  • ICP0-null herpes simplex type-1 viruses selectively target tumor cells with impaired PML signaling or IFN responsiveness.
  • Disruption of PML signaling in PML-positive cells sensitized them to oncolysis.
  • PML overexpression reversed the sensitivity to oncolysis, confirming PML's antiviral role.

Conclusions:

  • PML mediates an antiviral mechanism that predicts the tropism of IFN-sensitive oncolytic viruses.
  • ICP0-null herpes simplex type-1 viruses are the first anti-cancer therapeutics targeting deficiencies in PML expression.
  • This study highlights the potential of targeting PML pathways for developing selective oncolytic virotherapies.

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