Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis.
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.
Nguyên
Thi Lien-Anh
TL
Molecular Oncology Group, Lady Davis Institute-Jewish General Hospital, Montreal, QC, Canada.
Abdelbary
Hesham
H
Arguello
Meztli
M
Breitbach
Caroline
C
Leveille
Simon
S
Diallo
Jean-Simon
JS
Yasmeen
Amber
A
Bismar
Tarek A
TA
Kirn
David
D
Falls
Theresa
T
Snoulten
Valerie E
VE
Vanderhyden
Barbara C
BC
Werier
Joel
J
Atkins
Harold
H
Vähä-Koskela
Markus J V
MJ
Stojdl
David F
DF
Bell
John C
JC
Hiscott
John
J
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
D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; C118739:entinostat; D007372:Interferons