Transcriptional Modulation Using HDACi Depsipeptide Promotes Immune Cell-Mediated Tumor Destruction of Murine B16 Melanoma

Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical University, Shimotuke, Tochigi, Japan.
Journal of Investigative Dermatology (Impact Factor: 7.22). 06/2008; 128(6):1506-16. DOI: 10.1038/sj.jid.5701216
Source: PubMed


With melanoma, as with many other malignancies, aberrant transcriptional repression is a hallmark of refractory cancer. To restore gene expression, use of a histone deacetylase inhibitor (HDACi) is expected to be effective. Our recent DNA micro-array analysis showed that the HDACi depsipeptide (FK228) significantly enhances gp100 antigen expression. Herein, we demonstrate that depsipeptide promotes tumor-specific T-cell-mediated killing of B16/F10 murine melanoma cells. First, by a quantitative assay of caspase-3/7 activity, a sublethal dose of depsipeptide was determined (ED50: 5 nM), in which p21(Waf1/Cip1) and Fas were sufficiently evoked concomitantly with histone H3 acetylation. Second, the sublethal dose of depsipeptide treatment with either a recombinant Fas ligand or tumor-specific T cells synergistically enhanced apoptotic cell death in B16/F10 cells in vitro. Furthermore, we found that depsipeptide increased levels of perforin in T cells. Finally, in vivo metastatic growth of B16/F10 in the lung was significantly inhibited by a combination of depsipeptide treatment and immune cell adoptive transfer from immunized mice using irradiated B16 cells and gp100-specific (Pmel-1) TCR transgenic mice (P<0.05, vs cell transfer alone). Consequently, employment of a transcriptional modulation strategy using HDACis might prove to be a useful pretreatment for human melanoma immunotherapy.

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Available from: Takashi Murakami, Mar 18, 2014
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    • "Inhibition of histone deacetylases with HDACis, such as vorinostat, can preferentially induce cell cycle arrest, apoptosis, and differentiation in leukemic malignancies and solid tumors [12]. More importantly, HDACis have been shown to enhance tumor immunity by upregulating the expression of major histocompatibility class (MHC) molecules, costimulatory molecules and components involved in tumor necrosis factor (TNF) superfamily signaling [13-17]. However, HDACi’s have also been shown to increase the function of T regulatory cells and increase IDO immunosuppression by dendritic cells [18-20]. "
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    Full-text · Article · Apr 2014
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    • "C.B-17 SCID mice were treated by injection of anti-asialo GM1 Abs (100 mg/body, Wako, Japan) into the peritoneal cavity one day prior to the operation. For the subcutaneous injections, cells (1 × 106) were injected into the subcutaneous space of mice (the hind limb or the abdomen) [13], [36]. "
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