Hertie Institute for Clinical Brain Research and Center Neurology, Department of Vascular Neurology, Laboratory of Molecular Neuro-Oncology, Tübingen, Germany.
Anticancer Res. 2013 Apr;33(4):1351-60.
Histone deacetylase inhibitors (HDACi) have been described as multifunctional anticancer agents. The failure of conventional therapy for glioblastoma (GBM) renders this tumor an attractive target for immunotherapy. Innate immune cells, such as natural killer (NK) cells, play a crucial role in antitumor immune responses. Here, we describe how the HDACi trichostatin A (TSA) promotes apoptosis of tumor cells, as well as augments anti-GBM innate immune responses. In vitro treatment of GBM cells with TSA results in an up-regulation of the natural killer group-2 member-D (NKG2D) ligands major histocompatibility complex class I-related chain (MIC)-A and UL16 binding protein (ULBP)-2 at both mRNA and protein levels, rendering them susceptible to NK cell-mediated lysis. In vivo, TSA delays tumor growth of GBM xenografts. Both the in vitro and in vivo antitumor effect of TSA was significantly reduced by blocking NK cell activity. Our data suggest that HDACi, especially in combination with other clinical immunotherapeutical approaches, may be considered in a combined therapeutic approach for GBM.
组蛋白去乙酰化酶抑制剂（HDACi）被描述为具有多种功能的抗癌药物。由于胶质母细胞瘤（GBM）的常规治疗失败，这种肿瘤成为免疫治疗的一个有吸引力的靶点。先天免疫细胞，如自然杀伤（NK）细胞，在抗肿瘤免疫反应中发挥着至关重要的作用。在这里，我们描述了 HDACi 曲古抑菌素 A（TSA）如何促进肿瘤细胞凋亡，并增强抗 GBM 先天免疫反应。体外用 TSA 处理 GBM 细胞可导致主要组织相容性复合体 I 相关链（MIC）-A 和 UL16 结合蛋白（ULBP）-2 的 NKG2D 配体的 mRNA 和蛋白水平上调，使它们易受 NK 细胞介导的裂解。在体内，TSA 延迟 GBM 异种移植物的肿瘤生长。TSA 的体外和体内抗肿瘤作用均被阻断 NK 细胞活性显著降低。我们的数据表明，HDACi，尤其是与其他临床免疫治疗方法联合使用，可能被认为是 GBM 的联合治疗方法之一。
