Rescue of Major Histocompatibility-DR Surface Expression in Retinoblastoma-Defective, Non-small Cell Lung Carcinoma Cells by the MS-275 Histone Deacetylase Inhibitor

Abstract

Major histocompatibility (MHC) class II antigen presenting molecules play a seminal role on professional antigen presenting cells in the T-cell activation process and therefore in regulating the immune response. The role of MHC class II expression on tumor cells, particularly tumor cells of mesenchymal or parenchymal origin has been more controversial. Nevertheless, there is a large body of literature indicating that tumor cell MHC class II can affect tumor development. Tumor cell MHC class II expression has been shown to mediate tumor antigen dependent anti-tumor T-cell activity 1,2) ; to mediate apoptosis 3); and to mediate tolerance. 4)Furthermore, there are numerous tumor associated mechanisms, in some cases mechanisms that are indisputably associated with tumor development, involved in tumor cell regulation of MHC class II. For example, mitogen activated protein kinase (MAPK) activity in melanoma is associated with high levels of expression of human leukocyte antigen (HLA)-DR, the most important MHC class II molecule in humans. 5)Also, HLA-DR induction by interferon-gamma (IFN-g) is abolished or highly limited, depending on the cell type, in retinoblastoma protein (Rb)-defective tumor cells, including Rb-defective non-small cell lung cancer cells. 6-8)The histon deacetylase (HDAC) inhibitors, sodium butyrate and trichostatin A can induce MHC class II surface expression in tumor cells. 8,9) The requirement of IFN-g appears to be variable, but at a minimum, the combination of IFN-g treatment and the above HDAC inhibitors has always led to the rescue of MHC class II surface expression.10) However, this process has never been reported for a class I specific HDAC inhibitor and in particular has never been reported for an HDAC inhibitor in clinical trials. This is an important issue, because knowledge of the potential effect of an HDAC inhibitor, used for patient therapy, on MHC class II expression could affect the interpretations of clinical outcomes. The MS-275 class I HDAC inhibitor is currently being used in clinical trials for non-small cell lung cancer (http://clinicaltrials.gov/). Thus, we determined whether MS-275 could contribute to the induction of surface HLA-DR on non-small cell lung carcinoma cells. MATERIALS AND METHODSFor Fig. 2, H2009 non-small cell lung carcinoma cells were treated with 400 units IFN-g per ml for 48 h and analyzed by flow cytometry exactly as described.7) H2009 cells were cultured in RPMI, 10% fetal bovine serum, with pyruvate, penicillin, streptomycin and glutamate supplements. H2009 cells were treated with 1.6 mg/ml of MS-275 (Sigma-Aldrich) 24 h after the IFN-g treatment, i.e., for the last 24 h of the IFN-g treatment. For Fig. 3A, H2009 cells were transfected with the indicated plasmids and treated with IFN-g exactly as described.8) Cells were treated with 1.6 mg/ml of MS-275, as indicated, 4 h following the completion of the DNA transfection protocol. Luciferase assays were performed 24 h after completion of the DNA transfection protocol. Chromatin immunoprecipitation (ChIP)...

Gene expression-based prediction of myeloma cell sensitivity to histone deacetylase inhibitors

“…Investigating the HA Score in the eight groups of the molecular classification of MM (Zhan et al , 2006), HA Score was significantly higher in the proliferation subgroup ( P <0.001) associated with a poor prognosis and significantly lower in the CD2 subgroup ( P <0.001) (Zhan et al , 2006) (Figure 3). Among the 37 genes of the HA Score, 7 code for proteins that have been described as lysine acetylation target proteins and 18 have been identified as HDACi targets (Choudhary et al , 2009; Niesen and Blanck, 2009; Bantscheff et al , 2011; Iwahashi et al , 2011) (Supplementary Tables S5 and S6). Gene expression profiles of HA Score genes in purified MMC and normal BM subpopulations are listed in Supplementary Figure S2.…”

“…Among the current 95 genes deregulated by TSA treatment in HMCLs, 24 genes were commonly identified by Heller et al (2008) (Supplementary Table S4). Seven out of 37 HA Score genes code for proteins that have been described as lysine acetylation target proteins and 18 out of 37 HA Score genes have been identified as HDACi targets (Choudhary et al , 2009; Niesen and Blanck, 2009; Bantscheff et al , 2011; Iwahashi et al , 2011) (Supplementary Tables S5 and S6). …”

Histone deacetylase inhibitor enhances the anti-tumor effect of gemcitabine: A special reference to gene-expression microarray analysis

“…Many reports have documented the importance of histone acetylation as a positive regulator of MHC class II transcription (27,28) and HDAC inhibitors augmented the expression of the tumor cell MHC class II (29). On the other hand, HDAC activity repressed the MHC class II gene expression (30).…”

Cooperative Immune-Mediated Mechanisms of the HDAC Inhibitor Entinostat, an IL15 Superagonist, and a Cancer Vaccine Effectively Synergize as a Novel Cancer Therapy

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