title: Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis.
abstract: Intratumoral innate immunity can play a significant role in blocking the effective therapeutic spread of a number of oncolytic viruses (OVs). Histone deacetylase inhibitors (HDIs) are known to influence epigenetic modifications of chromatin and can blunt the cellular antiviral response. We reasoned that pretreatment of tumors with HDIs could enhance the replication and spread of OVs within malignancies. Here, we show that HDIs markedly enhance the spread of vesicular stomatitis virus (VSV) in a variety of cancer cells in vitro, in primary tumor tissue explants and in multiple animal models. This increased oncolytic activity correlated with a dampening of cellular IFN responses and augmentation of virus-induced apoptosis. These results illustrate the general utility of HDIs as chemical switches to regulate cellular innate antiviral responses and to provide controlled growth of therapeutic viruses within malignancies. HDIs could have a profoundly positive impact on the clinical implementation of OV therapeutics.
authors.affiliation: Molecular Oncology Group, Lady Davis Institute-Jewish General Hospital, Montreal, QC, Canada.
authors.forename: Thi Lien-Anh
authors.initials: TL
authors.lastname: Nguyên
authors.forename: Hesham
authors.initials: H
authors.lastname: Abdelbary
authors.forename: Meztli
authors.initials: M
authors.lastname: Arguello
authors.forename: Caroline
authors.initials: C
authors.lastname: Breitbach
authors.forename: Simon
authors.initials: S
authors.lastname: Leveille
authors.forename: Jean-Simon
authors.initials: JS
authors.lastname: Diallo
authors.forename: Amber
authors.initials: A
authors.lastname: Yasmeen
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Bismar
authors.forename: David
authors.initials: D
authors.lastname: Kirn
authors.forename: Theresa
authors.initials: T
authors.lastname: Falls
authors.forename: Valerie E
authors.initials: VE
authors.lastname: Snoulten
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Vanderhyden
authors.forename: Joel
authors.initials: J
authors.lastname: Werier
authors.forename: Harold
authors.initials: H
authors.lastname: Atkins
authors.forename: Markus J V
authors.initials: MJ
authors.lastname: Vähä-Koskela
authors.forename: David F
authors.initials: DF
authors.lastname: Stojdl
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
mesh_terms: D000818:Animals; D001549:Benzamides / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007372:Interferons / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy* / Q000821:virology; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000628:therapy / Q000821:virology; D011725:Pyridines / Q000627:therapeutic use; D018116:Vesiculovirus / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; C118739:entinostat; D007372:Interferons