HDAC inhibitors and immunotherapy; a double edged sword?
HDAC inhibitors and immunotherapy; a double edged sword?
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DOI：
10.18632/oncotarget.2289
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发表时间：
2014-08-30
期刊：
影响因子：
--
通讯作者：
Adema GJ
中科院分区：
文献类型：
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作者：
Kroesen M;Gielen P;Brok IC;Armandari I;Hoogerbrugge PM;Adema GJ
表观遗传修饰，如组蛋白乙酰化，是调节细胞内基因表达所必需的。癌细胞获得病理性表观遗传修饰，导致促进和维持肿瘤发生的基因表达模式。因此，表观遗传操作正在成为一种新的癌症靶向治疗方法。组蛋白乙酰化酶（HAT）和组蛋白去乙酰化酶（HDAC）调节组蛋白乙酰化并因此调节基因表达。组蛋白脱乙酰基酶（HDAC）抑制剂众所周知会影响癌细胞的活力和生物学，并且已经用于治疗癌症患者。免疫疗法可以在选定的癌症患者中产生临床益处，特别是在肿瘤减积后疾病有限的患者中。HDAC抑制剂可以通过消除肿瘤细胞而潜在地与免疫疗法协同作用。然而，HDAC抑制剂对免疫细胞功能的直接影响在很大程度上仍未被探索。最初的数据表明HDAC抑制剂主要是免疫抑制剂，但最近的报道挑战了这一观点。本文就HDAC抑制剂对肿瘤细胞和不同免疫细胞亚群的影响、协同作用及其可能机制进行综述。最后，我们将讨论HDAC抑制剂在癌症免疫联合治疗中的未来挑战和潜在应用。
Epigenetic modifications, like histone acetylation, are essential for regulating gene expression within cells. Cancer cells acquire pathological epigenetic modifications resulting in gene expression patterns that facilitate and sustain tumorigenesis. Epigenetic manipulation therefore is emerging as a novel targeted therapy for cancer. Histone Acetylases (HATs) and Histone Deacetylases (HDACs) regulate histone acetylation and hence gene expression. Histone deacetylase (HDAC) inhibitors are well known to affect cancer cell viability and biology and are already in use for the treatment of cancer patients. Immunotherapy can lead to clinical benefit in selected cancer patients, especially in patients with limited disease after tumor debulking. HDAC inhibitors can potentially synergize with immunotherapy by elimination of tumor cells. The direct effects of HDAC inhibitors on immune cell function, however, remain largely unexplored. Initial data have suggested HDAC inhibitors to be predominantly immunosuppressive, but more recent reports have challenged this view. In this review we will discuss the effects of HDAC inhibitors on tumor cells and different immune cell subsets, synergistic interactions and possible mechanisms. Finally, we will address future challenges and potential application of HDAC inhibitors in immunocombination therapy of cancer.