Topper Michael J, Vaz Michelle, Chiappinelli Katherine B, DeStefano Shields Christina E, Niknafs Noushin, Yen Ray-Whay Chiu, Wenzel Alyssa, Hicks Jessica, Ballew Matthew, Stone Meredith, Tran Phuoc T, Zahnow Cynthia A, Hellmann Matthew D, Anagnostou Valsamo, Strissel Pamela L, Strick Reiner, Velculescu Victor E, Baylin Stephen B
Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA; The Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA.
Cell. 2017 Nov 30;171(6):1284-1300.e21. doi: 10.1016/j.cell.2017.10.022.
Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/β-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYC signaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion state towards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcoming clinical trial, testing enhancement of immune checkpoint therapy for NSCLC.
将DNA去甲基化剂（DNA甲基转移酶抑制剂[DNMTis]）与组蛋白脱乙酰酶抑制剂（HDACis）联合使用有望增强癌症免疫治疗效果。在此，对HDACis的药理学和亚型特异性进行了研究，以指导将其添加到DNMTi中，从而设计出一种新的低剂量序贯方案，该方案对非小细胞肺癌（NSCLC）具有强大的抗肿瘤作用。利用体外处理的NSCLC细胞系，我们阐明了一种基于干扰素α/β的转录程序，同时抗原呈递机制上调，部分通过双链RNA（dsRNA）诱导介导。这伴随着MYC信号传导的抑制和T细胞趋化因子CCL5的增加。在NSCLC小鼠模型中使用这种联合治疗方案可逆转肿瘤免疫逃逸，并将T细胞耗竭状态调节为记忆和效应T细胞表型。即将开展的一项临床试验出现了关键的相关科学指标，该试验旨在测试NSCLC免疫检查点治疗的增强效果。
