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 Geoffrey Vile, Alan A. Melcher, Fiona Errington-Mais

Research output: Contribution to journalArticle

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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 (HSV GM-CSF ) alone and in combination with histone deacetylase inhibition. We found that HSV GM-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 HSV GM-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. Jennings et al., demonstrate that oncolytic HSV GM-CSF activates NK cells and matures immature dendritic cells to promote cytotoxic T lymphocyte (CTL) priming. Moreover, they report that histone deacetylase inhibition can augment innate and adaptive anti-tumor immune responses through increased expression of NK cell-activating ligands and tumor-associated antigens.

Original languageEnglish (US)
JournalMolecular Therapy
DOIs
StatePublished - Jan 1 2019

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Oncolytic Viruses
Histone Deacetylases
Granulocyte-Macrophage Colony-Stimulating Factor
Simplexvirus
Natural Killer Cells
Cytotoxic T-Lymphocytes
Immunity
Melanoma
Neoplasms
Valproic Acid
Neoplasm Antigens
Dendritic Cells
Ligands
Interferon Type I
Histone Deacetylase Inhibitors
Antigen-Presenting Cells
Monocytes

Keywords

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

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., ... Errington-Mais, F. (2019). Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition. Molecular Therapy. https://doi.org/10.1016/j.ymthe.2019.04.008

Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition. / Jennings, Victoria A.; Scott, Gina B.; Rose, Ailsa M.S.; Scott, Karen J.; Migneco, Gemma; Keller, Brian; Reilly, Katrina; Donnelly, Oliver; Peach, Howard; Dewar, Donald; Harrington, Kevin J.; Pandha, Hardev; Samson, Adel; Vile, Richard Geoffrey; Melcher, Alan A.; Errington-Mais, Fiona.

In: Molecular Therapy, 01.01.2019.

Research output: Contribution to journalArticle

Jennings, VA, Scott, GB, Rose, AMS, Scott, KJ, Migneco, G, Keller, B, Reilly, K, Donnelly, O, Peach, H, Dewar, D, Harrington, KJ, Pandha, H, Samson, A, Vile, RG, Melcher, AA & Errington-Mais, F 2019, 'Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition', Molecular Therapy. https://doi.org/10.1016/j.ymthe.2019.04.008
Jennings, Victoria A. ; Scott, Gina B. ; Rose, Ailsa M.S. ; Scott, Karen J. ; Migneco, Gemma ; Keller, Brian ; Reilly, Katrina ; Donnelly, Oliver ; Peach, Howard ; Dewar, Donald ; Harrington, Kevin J. ; Pandha, Hardev ; Samson, Adel ; Vile, Richard Geoffrey ; Melcher, Alan A. ; Errington-Mais, Fiona. / Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition. In: Molecular Therapy. 2019.
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