Essential role of HDAC6 in the regulation of PD-L1 in melanoma.
Essential role of HDAC6 in the regulation of PD-L1 in melanoma.
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DOI：
10.1016/j.molonc.2015.12.012
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发表时间：
2016-05
影响因子：
6.6
通讯作者：
A V
中科院分区：
文献类型：
--
作者：
M L;P PV;T K;M P;E S;J P;K V W;C L;F C;S D;M SKS;M M;A K;J PI;A S;E S;J W;E M S;A V
组蛋白去乙酰化酶（HDAC），最初被描述为组蛋白修饰剂，最近已被证明靶向各种其他蛋白质无关的染色质环境。在这种情况下，我们目前的工作表明，原发性黑色素瘤样品和细胞系中HDAC 6的药理学或遗传学废除下调了PD-L1的表达，PD-L1是癌细胞中表达的一种重要的共刺激分子，其激活了T细胞中的抑制性调节途径PD-1。我们的数据表明，PD-L1调节的这种新机制主要是由HDAC 6对STAT 3的募集和激活的影响介导的。此外，我们观察到，选择性HDAC 6抑制剂损害肿瘤生长，并减少几种抑制性检查点分子和其他参与免疫监视的调节途径的体内表达。最重要的是，这些结果为进一步研究同种型选择性HDAC 6抑制剂作为癌症中潜在的免疫调节剂提供了关键的临床前原理和依据。
Histone deacetylases (HDACs), originally described as histone modifiers, have more recently been demonstrated to target a variety of other proteins unrelated to the chromatin environment. In this context, our present work demonstrates that the pharmacological or genetic abrogation of HDAC6 in primary melanoma samples and cell lines, down-regulates the expression of PD-L1, an important co-stimulatory molecule expressed in cancer cells, which activates the inhibitory regulatory pathway PD-1 in T-cells. Our data suggests that this novel mechanism of PD-L1 regulation is mainly mediated by the influence of HDAC6 over the recruitment and activation of STAT3. Additionally, we observed that selective HDAC6 inhibitors impairs tumor growth and reduce the in vivo expression of several inhibitory check point molecules and other regulatory pathways involved in immunosurveillance. Most importantly, these results provide a key pre-clinical rationale and justification to further study isotype selective HDAC6 inhibitors as potential immunomodulatory agents in cancer.