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 antitumor immunity and demonstrate their therapeutic potential for treatment of NSCLC.

Significance: Selective inhibition of HDACs and bromodomain proteins modulates tumor-associated immune cells in a manner that favors improved T-cell function and reduced inhibitory cellular mechanisms. These effects facilitated robust antitumor responses in tumor-bearing mice, demonstrating the therapeutic potential of combining these epigenetic modulators for the treatment of NSCLC. Cancer Discov; 7(8); 852–67. ©2017 AACR.

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尽管对体细胞改变的致癌途径有了越来越广泛的了解，但非小细胞肺癌（NSCLC）的有效疗法仍然具有挑战性。现在清楚的是，有可能影响肿瘤免疫微环境的治疗剂增强了免疫协调的治疗益处。本文中，我们评估了组蛋白脱乙酰基酶（HDAC）和溴结构域抑制剂（调节表观基因组的两类药物）的免疫调节特性，重点研究了参与免疫应答的关键细胞亚群。通过评估人类外周血和NSCLC肿瘤，我们表明选择性HDAC6抑制剂ricolinostat促进支持增强的T细胞活化和抗原呈递细胞功能改善的表型变化。溴结构域抑制剂JQ1减毒CD4 ⁺FOXP3 ⁺ T调节性细胞具有抑制功能，并与蓖麻抑菌剂协同作用，以促进免疫介导的肿瘤生长停滞，从而延长了肺腺癌小鼠的生存期。总的来说，我们的发现突出了两种表观遗传修饰剂的免疫调节作用，二者共同促进了T细胞介导的抗肿瘤免疫力，并证明了其治疗非小细胞肺癌的治疗潜力。

意义： HDAC和溴结构域蛋白的选择性抑制以有利于改善T细胞功能和减少抑制性细胞机制的方式调节肿瘤相关免疫细胞。这些作用促进了荷瘤小鼠的强烈抗肿瘤反应，证明了将这些表观遗传调节剂联合用于治疗非小细胞肺癌的治疗潜力。巨蟹座Discov; 7（8）；852–67。©2017 AACR。

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