Histone Deacetylase Inhibition Modulates Adaptive and Innate Immunity
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Date
2010-06
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The Ohio State University
Abstract
Epigenetic gene silencing has been associated with the onset and progression of a wide range of diseases, including cancer. Histone deacetylase enzymes (HDAC) influence the epigenome by covalently modifying histone tails promoting tighter nucleosomal structure and transcriptional silencing. Consequently, drugs that inhibit HDAC enzymes hold significant promise as specific and effective therapeutic agents. While HDAC inhibitors are presently being evaluated in clinical trials, little is known regarding the effects of HDAC inhibition on host immunity. Here we report that the broad spectrum HDAC inhibitor AR-42 (Arno Pharmaceuticals) exerts a dose-dependent inhibitory effect on innate and adaptive immune function. The observed inhibition of NK and T cell cytotoxicity occurred at concentrations (100 – 500nM) below the range found to elicit anti tumor activity against Epstein-Barr Virus (EBV)-transformed lymphoblastoid cell lines (LCL). Overnight incubation of purified NK cells in low doses of AR-42 also inhibited antibody dependent cellular cytotoxicity (ADCC) against rituximab-coated EBV+ LCLs. Overnight incubation of effector and LCL target cells in low doses of AR-42 (100 – 500nM) modulated expression of key regulatory proteins involved with cellular and adaptive immune responses (NKG2D, KIR, NKp46, NKp30, MHC I). AR-42 led to decreased granzyme B (GzB) and interferon-gamma (IFNy) release by activated NK and T cells. Similar effects with IFNy and GzB production were seen with the broad spectrum HDAC inhibitors SAHA and valproate, however, NK cell cytotoxic potential remained unchanged with these two HDAC inhibitors. Washout of AR-42 from cell cultures led to significant recovery of cytotoxic activity and IFNy release from both NK and T cell effectors suggesting that the inhibitory effect is transient, fully reversible and comparable to vehicle (DMSO) treated effector cells. The differential effects observed with SAHA and VPA on cytotoxicity and cytokine release suggests individual HDAC inhibitor drugs may exhibit distinct immune-modulatory profiles. The data suggest broad spectrum class I and II HDAC inhibitors suppress the adaptive and innate immune responses and highlight the importance of performing immune laboratory correlative studies as these drugs are evaluated in clinical trials.
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Keywords
cancer therapeutic, histone deacetylase inhibition, natural killer cytotoxicity, ctl cytotoxicity, epstein-barr virus, lymphoma