Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer.
Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer.
复制标题
组蛋白脱乙酰酶和 Bromodomain 联合抑制对非小细胞肺癌的协同免疫刺激作用和治疗效果。
DOI：
10.1158/2159-8290.cd-16-1020
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发表时间：
2017-08
期刊：
影响因子：
28.2
通讯作者：
Wong KK
中科院分区：
文献类型：
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作者：
Adeegbe DO;Liu Y;Lizotte PH;Kamihara Y;Aref AR;Almonte C;Dries R;Li Y;Liu S;Wang X;Warner-Hatten T;Castrillon J;Yuan GC;Poudel-Neupane N;Zhang H;Guerriero JL;Han S;Awad MM;Barbie DA;Ritz J;Jones SS;Hammerman PS;Bradner J;Quayle SN;Wong KK
非小细胞肺癌（NSCLC）的有效治疗仍然具有挑战性，尽管越来越全面的了解体细胞改变致癌途径。现在清楚的是，具有影响肿瘤免疫微环境潜力的治疗剂增强免疫协调的治疗益处。在本文中，我们评估了组蛋白脱乙酰酶（HDAC）和布罗莫结构域抑制剂的免疫调节特性，这两类药物调节表观基因组，重点是参与免疫应答的关键细胞亚群。通过评估人外周血和NSCLC肿瘤，我们表明选择性HDAC6抑制剂ricolinostat促进表型变化，支持增强的T细胞活化和改善的抗原呈递细胞功能。布罗莫结构域抑制剂JQ1减弱了CD4+Foxp3+ T调节细胞的抑制功能，并与ricolinostat协同作用，促进免疫介导的肿瘤生长停滞，导致肺腺癌小鼠的生存期延长。总的来说，我们的研究结果强调了两种表观遗传修饰剂的免疫调节作用，它们共同促进T细胞介导的抗肿瘤免疫，并证明了它们治疗NSCLC的治疗潜力。
Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T cell activation and improved function of antigen presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+Foxp3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight the immunomodulatory effects of two epigenetic modifiers that, together, promote T cell-mediated anti-tumor immunity and demonstrate their therapeutic potential for treatment of NSCLC.