Transcriptional modulation using HDACi depsipeptide promotes immune cell-mediated tumor destruction of murine B16 melanoma
Transcriptional modulation using HDACi depsipeptide promotes immune cell-mediated tumor destruction of murine B16 melanoma
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DOI：
10.1038/sj.jid.5701216
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发表时间：
2008-06-01
影响因子：
6.5
通讯作者：
Kobayashi, Eiji
中科院分区：
文献类型：
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作者：
Murakami, Takashi;Sato, Atsuko;Kobayashi, Eiji
与许多其他恶性肿瘤一样，黑色素瘤的异常转录抑制是难治性癌症的标志。为了恢复基因表达，使用组蛋白脱乙酰酶抑制剂（HDACi）预期是有效的。我们最近的DNA微阵列分析表明，HDACi缩肽（FK 228）显着增强gp 100抗原表达。在此，我们证明缩肽促进肿瘤特异性T细胞介导的B16/F10鼠黑色素瘤细胞的杀伤。首先，通过半胱天冬酶-3/7活性的定量测定，确定缩肽的亚致死剂量（ED 50：5 nM），其中p21（Waf 1/Cip 1）和Fas伴随组蛋白H3乙酰化被充分诱发。其次，亚致死剂量的缩肽处理与重组Fas配体或肿瘤特异性T细胞协同增强B16/F10细胞的体外凋亡性细胞死亡。此外，我们发现缩肽增加了T细胞中穿孔素的水平。最后，通过缩肽处理和免疫细胞过继转移的组合，B16/F10在肺中的体内转移性生长被显著抑制（P < 0.05，相对于单独的细胞转移），所述免疫细胞过继转移来自使用辐射的B16细胞和gp 100特异性（Pmel-1）TCR转基因小鼠的免疫小鼠。因此，使用HDACis的转录调节策略的就业可能被证明是一个有用的人黑色素瘤免疫治疗的预处理。
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.