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

Abstract

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-␥) 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. Despite intense investigations to improve the standard of therapy for glioblastoma (GBM), current regimens result in approximately 15 months of median survival following initial diagnosis, emphasizing the need for new therapies. Oncolytic viruses (OV) are promising biological agents, intensely investigated for nearly 2 decades. These naturally occurring and biologically engineered viruses, which are designed to replicate in a relatively selective manner within tumors and culminate in the destruction of the host's cancer cells (1, 10), have demonstrated effectiveness in preclinical models. Five different clinical trials have tested oncolytic herpes simplex virus (oHSV) (22,35,36,47,50), and a maximum tolerated dose was not achieved and toxicity was not demonstrated. Additionally, oncolytic adenovirus (11), Newcastle disease virus (16), and reovirus (14) have been shown to be safe in dose escalation trials in humans with malignant glioma; moreover, there are ongoing clinical trials with measles virus (24), retrovirus (45), parvovirus H-1, poliovirus, and Seneca Valley virus (see http://www.clinicaltrials.gov/ct2 /results?termϭglioblastomaϩANDϩvirus). However, therapeutic efficacy has been elusive to demonstrate. It is evident that efficacy should depend on the ability of the initially injected oHSV to replicate and distribute within the GBM mass. Identification of both barriers in the host that could li...

Induction of Glycosphingolipid GM3 Expression by Valproic Acid Suppresses Cancer Cell Growth

“…Valproic acid is a known histone deacetylase inhibitor (14,15), and expression of several genes (including ST3GAL5) has been shown to be altered by valproic acid treatment (14,16). Many mechanisms have been proposed to explain the antitumor effect of valproic acid (25,26). We believe that the results of our study provide further evidence that valproic acid has antitumor activity.…”

682: Synergistic combination of valproic acid and oncolytic parvovirus H-1PV as a potential therapy against cervical and pancreatic carcinomas

“…In particular, valproic acid (VPA), already used clinically as an antiepileptic agent, is being tested as anticancer agent in a phase III clinical trial for cervical carcinomas (Coronel et al, 2010;Gottlicher et al, 2001). HDACIs have also been shown to reinforce the cytotoxicity of oncolytic viruses, including the vesicular stomatitis virus (VSV; Alvarez-Breckenridge et al, 2012), herpes simplex virus (HSV; Otsuki et al, 2008) and adenoviruses (VanOosten et al, 2007), by repressing the expression of host cell genes involved in the antiviral immune response or by stimulating the expression of genes required for the viral life cycle (Nguyen et al, 2010).…”

Potentiating oncolytic viral therapy through an understanding of the initial immune responses to oncolytic viral infection

“…Of the various HDACi, valproic acid (VPA) has been shown to enhance the efficacy of oncolytic HSV through the inhibition of IFN-I, STAT-1, PKR, and PML signaling within infected glioblastoma cells [58] while trichostatin A (TSA) promoted viral oncolysis through cell cycle arrest with cyclin D1 degradation and VEGF inhibition [59]. Beyond targeting the intracellular mediators that are responsible for creating an antiviral state, VPA cotherapy has also been demonstrated to suppress NK cell and macrophage recruitment and activation following OV HSV treatment [47]. Moreover, VPA mediated suppression of IFN-g production from NK cells was mediated in a Stat5/T-bet dependent fashion [47].…”

“…Beyond targeting the intracellular mediators that are responsible for creating an antiviral state, VPA cotherapy has also been demonstrated to suppress NK cell and macrophage recruitment and activation following OV HSV treatment [47]. Moreover, VPA mediated suppression of IFN-g production from NK cells was mediated in a Stat5/T-bet dependent fashion [47].…”