Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition

Victoria A. Jennings, Gina B. Scott, Ailsa M.S. Rose, Karen J. Scott, Gemma Migneco, Brian Keller, Katrina Reilly, Oliver Donnelly, Howard Peach, Donald Dewar, Kevin J. Harrington, Hardev Pandha, Adel Samson, Richard G. Vile, Alan A. Melcher, Fiona Errington-Mais

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

A clinical oncolytic herpes simplex virus (HSV)encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), talimogene laherparepvec, causes regression of injected and non-injected melanoma lesions in patients and is now licensed for clinical use in advanced melanoma. To date, limited data are available regarding the mechanisms of human anti-tumor immune priming, an improved understanding of which could inform the development of future combination strategies with improved efficacy. This study addressed direct oncolysis and innate and adaptive human immune-mediated effects of a closely related HSV encoding GM-CSF (HSVGM-CSF)alone and in combination with histone deacetylase inhibition. We found that HSVGM-CSF supported activation of anti-melanoma immunity via monocyte-mediated type I interferon production, which activates NK cells, and viral maturation of immature dendritic cells (iDCs)into potent antigen-presenting cells for cytotoxic T lymphocyte (CTL)priming. Addition of the histone deacetylase inhibitor valproic acid (VPA)to HSVGM-CSF treatment of tumor cells increased viral replication, viral GM-CSF production, and oncolysis and augmented the development of anti-tumor immunity. Mechanistically, VPA increased expression of activating ligands for NK cell recognition and induced expression of tumor-associated antigens, supporting innate NK cell killing and CTL priming. These data support the clinical combination of talimogene laherparepvec with histone deacetylase inhibition to enhance oncolysis and anti-tumor immunity.

Original languageEnglish (US)
Pages (from-to)1139-1152
Number of pages14
JournalMolecular Therapy
Volume27
Issue number6
DOIs
StatePublished - Jun 5 2019

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Keywords

  • HSV,cancer immunotherapy
  • VPA
  • herpes simplex virus
  • histone deacetylase inhibitor
  • oncolytic virus
  • valproic acid

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Jennings, V. A., Scott, G. B., Rose, A. M. S., Scott, K. J., Migneco, G., Keller, B., Reilly, K., Donnelly, O., Peach, H., Dewar, D., Harrington, K. J., Pandha, H., Samson, A., Vile, R. G., Melcher, A. A., & Errington-Mais, F. (2019). Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition. Molecular Therapy, 27(6), 1139-1152. https://doi.org/10.1016/j.ymthe.2019.04.008