JQ 1 是一种选择性溴结构域抑制剂，可降低抗原呈递细胞 (APC) 中致耐受分子 PDL1 的表达并恢复无能 CD4+ T 细胞的反应性,Blood

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JQ 1 是一种选择性溴结构域抑制剂，可降低抗原呈递细胞 (APC) 中致耐受分子 PDL1 的表达并恢复无能 CD4+ T 细胞的反应性
Blood ( IF 21.0 ) Pub Date : 2014-12-06 , DOI: 10.1182/blood.v124.21.2749.2749
Hongwei Wang ₁ , Fengdong Cheng ₁ , Limin Xing ₂ , Xiaohong Zhao ₁ , Alejandro Villagra ₁ , Javier Pinilla-Ibarz ₁ , Jianguo Tao ₁

Affiliation

Bromodomain and extraterminal (BET) 是一种蛋白质结构域，可识别乙酰化赖氨酸残基，例如组蛋白 N 末端尾部的残基。这种识别通常是蛋白质-组蛋白关联、染色质重塑和基因转录的先决条件。BET 蛋白在通过组蛋白标记的翻译调节炎症细胞因子基因反应中的作用知之甚少。鉴于 APC 的炎症状态对于确定 T 细胞激活与 T 细胞耐受性至关重要，并且 APC 中特定基因的表观遗传修饰在此过程中起着关键作用，我们最近确定了抑制 APC 中 BET 的功能后果. 首先，我们评估了 JQ 1 的效果，选择性小分子 BET 溴结构域抑制剂对 APC 的功能及其对抗原特异性 CD4+ T 细胞反应的调节。体外治疗腹膜引发的巨噬细胞 (PEM) 或骨髓衍生的树突细胞 (DC)，增加浓度的 JQ 1 导致抗炎细胞因子 IL-10 和 IL-6 的表达和蛋白质产生减少，以响应 LPS 刺激. 在使用的浓度下，JQ 1 不影响处理过的 APC 的活力。其次，对 MHC 类分子和共刺激分子表达的分析表明，与未处理的 APC 相比，经 JQ 1 处理的 APC 中致耐受性 PDL1 分子的表达降低。第三，我们评估了 JQ 1 处理的 APC 将同源抗原呈递给初始或耐受抗原特异性 CD4+ T 细胞的能力。我们发现用 JQ 1 处理 PEM 或 DC 增强了它们的抗原呈递能力，导致幼稚 CD4+ T 细胞的有效启动，这通过它们响应同源抗原而增加的 IL-2 和 IFN-γ 产生得到证实。更重要的是，经 JQ 1 处理的 APC 能够恢复从携带淋巴瘤的宿主中分离的耐受 CD4+ T 细胞的反应性。总之，我们发现用溴结构域特异性抑制剂 JQ 1 处理的 APC 更具炎症性，免疫抑制分子 PDL1 的表达较低，更重要的是，能够恢复耐受性 T 细胞的反应性。因此，我们的研究揭示了 BET 抑制剂以前未知的免疫学作用，并拓宽了它们作为癌症免疫治疗有前景的佐剂的临床范围。

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JQ 1, a Selective Bromodomain Inhibitor, Decreased the Expression of the Tolerogenic Molecule PDL1 in Antigen-Presenting Cells (APCs) and Restores the Responsiveness of Anergic CD4+ T Cells

Bromodomain and extraterminal (BET) is a protein domain that recognizes acetylated lysine residues such as those on the N-terminal tails of histones. This recognition is often a prerequisite for protein-histone association, chromatin remodeling and gene transcription. The role of BET proteins in regulating the response of inflammatory cytokine genes through translation of histone marks is poorly understood. Given that the inflammatory status of the APC is critical in determining T-cell activation versus T-cell tolerance and that epigenetic modifications of specific genes in the APC play a key role in this process, we recently determined the functional consequences of inhibiting BET in APCs. First, we evaluated the effects of JQ 1, a selective small-molecule BET bromodomain inhibitor on APC’s function and its regulation of antigen-specific CD4+ T-cells response. In vitro treatment of peritoneal elicited macrophages (PEM) or bone marrow derived dendritic cells (DCs) with increasing concentrations of JQ 1 resulted in decreased expression and protein production of the anti-inflammatory cytokine IL-10 and IL-6 in response to LPS stimulation. At the concentration used, JQ 1 did not affect the viability of treated APCs. Second, analysis of the expression of MHC class molecules and co-stimulatory molecules revealed a decreased expression of the tolerogenic PDL1 molecule in JQ 1- treated APCs as compared to untreated APCs. Third, we evaluated the ability of JQ 1 treated APCs to present cognate antigen to naive or tolerant antigen-specific CD4+ T-cells. We found that treatment of either PEM or DC with JQ 1 enhanced their antigen-presenting capabilities leading to effective priming of naive CD4+ T-cells confirmed by their increased production of IL-2 and IFN-gamma in response to cognate antigen. More importantly, JQ 1- treated APCs were able to restore the responsiveness of tolerant CD4+ T-cells isolated from lymphoma bearing hosts. Taken together, we have found that APCs treated with the Bromodomain specific inhibitor JQ 1 are more inflammatory, display lower expression of the immunosuppressive molecule PDL1 and more importantly, are capable of restoring the responsiveness of tolerant T-cells. Our studies therefore have unveiled a previously unknown immunological effect of BET inhibitors and have broadened their clinical scope as promising adjuvants in cancer immunotherapy. Disclosures No relevant conflicts of interest to declare.

更新日期：2014-12-06

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