Transcriptional modulation using HDACi depsipeptide promotes immune cell-mediated tumor destruction of murine B16 melanoma
J Invest Dermatol
T. Murakami, A. Sato, N. A. Chun, M. Hara, Y. Naito, Y. Kobayashi, Y. Kano, M. Ohtsuki, Y. Furukawa, E. KobayashiWith 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.
2008
J Invest Dermatol
Volume: 128. Issue: 6. Pages: 1506-16.
