NK Cell Recognition of Hepatocellular Carcinoma by Specific Induction of NKG2D Ligands Following Treatment with the Histone Deacetylase Inhibitor Sodium Valproate.

Histone deacetylase inhibitors (HDAC-I) are currently being evaluated as novel treatment for various malignancies. Recently, the HDAC-I sodium valproate (VPA) was shown to exert anti-neoplastic effects on human hepatoma cells while being well tolerated by primary human hepatocytes (PHH). However, the mechanisms underlying this differential mode of action are unclear. In this study, we used microarray analysis to unravel alterations of genes in hepatoma cells upon treatment with VPA. VPA induced the transcription of MICA and MICB, the ligands of the activating immunoreceptor NKG2D which is expressed on cytotoxic lymphocytes and has been shown to play a central role in the immune surveillance of tumors. Changes in MIC mRNA were mirrored by an increase of cell surface, soluble and total MIC protein as determined by immunofluorescense, flow cytometry and ELISA techniques. No significant changes of the NKG2D ligands (NKG2DL) ULBP1-3 were observed. Most importantly, VPA treatment did not induce MIC protein expression in PHH. The VPA-induced MIC expression profoundly triggered lysis of hepatoma cells by NK92 NK cells, which was abrogated by addition of a NKG2D antibody. Since the strength of an anti-tumor response by NK cells and CD8 T cells is critically depending on NKG2DL expression levels and the HDAC-I VPA mediates lysis of hepatoma cells via specific induction of NKG2DL, our results suggest a potential use of VPA in priming tumor cells for innate immune effector mechanisms.