The histone deacetylase inhibitor valproic acid lessens NK cell action against oncolytic virus-infected glioblastoma cells by inhibition of STAT5/T-BET signaling and generation of gamma interferon.
Tumor virotherapy has been and continues to be used in clinical trials. One barrier to effective viral oncolysis, consisting of the interferon (IFN) response induced by viral infection, is inhibited by valproic acid (VPA) and other histone deacetylase inhibitors (HDACi). Innate immune cell recruitment and activation have been shown to be deleterious to the efficacy of oncolytic herpes simplex virus (oHSV) infection, and in this report we demonstrate that VPA limits this deleterious response. VPA, administered prior to oHSV inoculation in an orthotopic glioblastoma mouse model, resulted in a decline in NK and macrophage recruitment into tumor-bearing brains at 6 and 24 h post-oHSV infection. Interestingly, there was a robust rebound of recruitment of these cells at 72 h post-oHSV infection. The observed initial decline in immune cell recruitment was accompanied by a reduction in their activation status. VPA was also found to have a profound immunosuppressive effect on human NK cells in vitro. NK cytotoxicity was abrogated following exposure to VPA, consistent with downmodulation of cytotoxic gene expression of granzyme B and perforin at the mRNA and protein levels. In addition, suppression of gamma IFN (IFN-γ) production by VPA was associated with decreased STAT5 phosphorylation and dampened T-BET expression. Despite VPA-mediated immune suppression, mice were not at significantly increased risk for HSV encephalitis. These findings indicate that one of the avenues by which VPA enhances oHSV efficacy is through initial suppression of immune cell recruitment and inhibition of inflammatory cell pathways within NK cells.
Medical Scientist Training Program, The Ohio State University Medical Center and The James Cancer Hospital and Solove Research Institute, Columbus, Ohio, USA.
Christopher A
CA
Alvarez-Breckenridge
Jianhua
J
Yu
Richard
R
Price
Min
M
Wei
Yan
Y
Wang
Michal O
MO
Nowicki
Yoonhee P
YP
Ha
Stephen
S
Bergin
Christine
C
Hwang
Soledad A
SA
Fernandez
Balveen
B
Kaur
Michael A
MA
Caligiuri
E Antonio
EA
Chiocca
D000818:Animals; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D018139:Simplexvirus / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors*; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D000098815:T-bet Transcription Factor
D056572:Histone Deacetylase Inhibitors; D050799:STAT5 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014635:Valproic Acid; D007371:Interferon-gamma