Landscape of immune-related signatures induced by targeting of epigenetic regulators in melanoma II

Epigenetic drugs exert a wide range of immune-related effects, but have strong drug-specific heterogeneity in immunomodulation, thus hampering selection of the most promising agent for innovative cancer immunotherapy approaches. Here we identified immune-related signatures induced by four classes of epigenetic drugs in melanoma cells to define the most active agent and to understand its biological activity in -vitro, in a pre-clinical model and in clinical samples. Gene modulation, induced by inhibitors of DNA methyltransferases (guadecitabine), histone deacetylases (givinostat), bromodomain and extraterminal domain proteins (JQ1 and OTX-015) and enhancer of zeste homolog 2 (GSK126), was assessed in human melanoma cell lines. All drugs modulated genes belonging to 20 families. Guadecitabine, followed by givinostat, was the most active drug and upregulated >160 immune-related genes characterized by low expression and high methylation. JQ1 and OTX-015 showed predominant inhibitory effects, GSK126 was the least active. A dominant immunomodulatory effect of guadecitabine and JQ1 was observed in combinatorial treatments. This experiment deals with the characterization of gene modulation by epigenetic drugs (guadecitabine, givinostat, JQ1, GSK-126) and by the unrelated drug Abemaciclib in two melanoma cells lines CST30 and VRG100 Whole genome gene expression was assessed by Clariom S arrays in two cell lines CST30 and VRG100 treated or not with epigenetic drugs.

表观遗传药物（epigenetic drugs）可介导多种免疫相关效应，但在免疫调节过程中表现出显著的药物特异性异质性，这一特性阻碍了创新性癌症免疫治疗方案中最优候选药物的筛选。本研究鉴定了四类表观遗传药物在黑色素瘤细胞中诱导的免疫相关特征，旨在明确活性最强的药物，并阐明其在体外、临床前模型及临床样本中的生物学活性。我们对靶向DNA甲基转移酶（DNA methyltransferases）的抑制剂guadecitabine、靶向组蛋白去乙酰化酶（histone deacetylases）的抑制剂givinostat、靶向溴结构域与额外末端结构域蛋白（bromodomain and extraterminal domain proteins）的抑制剂JQ1与OTX-015，以及靶向zeste同源物2增强子（enhancer of zeste homolog 2）的抑制剂GSK126在人黑色素瘤细胞系中的基因调控效应进行了检测。所有受试药物均可调控隶属于20个基因家族的基因。其中，guadecitabine活性最强，其次为givinostat，二者可上调超过160个低表达且高甲基化的免疫相关基因。JQ1与OTX-015主要表现为基因抑制效应，而GSK126的活性最弱。联合给药时，guadecitabine与JQ1展现出显著的免疫调节协同效应。本实验旨在表征表观遗传药物（guadecitabine、givinostat、JQ1、GSK-126）及无关药物Abemaciclib在两种黑色素瘤细胞系CST30与VRG100中的基因调控效应。采用Clariom S基因芯片对经或未经上述药物处理的该两种细胞系进行全基因组基因表达检测。