Reducing TNF Receptor 2+ Regulatory T Cells via the Combined Action of Azacitidine and the HDAC Inhibitor, Panobinostat for Clinical Benefit in Acute Myeloid Leukemia Patients
Reducing TNF Receptor 2+ Regulatory T Cells via the Combined Action of Azacitidine and the HDAC Inhibitor, Panobinostat for Clinical Benefit in Acute Myeloid Leukemia Patients
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DOI：
10.1158/1078-0432.ccr-13-1576
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发表时间：
2014-02-01
影响因子：
11.5
通讯作者：
Plebanski, Magdalena
中科院分区：
文献类型：
--
作者：
Govindaraj, Chindu;Tan, Peter;Plebanski, Magdalena
目的：急性髓性白血病（AML）提供了一个环境，使免疫抑制，导致功能缺陷的效应T细胞;调节性T细胞（Treg）是抗肿瘤免疫反应受损的重要贡献者。由于TNF在AML中以高水平存在，并且表达TNF受体-2（TNFR 2）的T细胞识别出高功能性T细胞，因此我们检查了TNFR 2（+）T细胞是这种癌症中相关Treg亚群的假设。我们还确定了去甲基化剂阿扎胞苷与组蛋白去乙酰化酶抑制剂帕比司他的新型组合疗法对TGFR 2，特别是TNFR 2（+）TGFR 2的影响。患者接受阿扎胞苷和帕比司他治疗，28天为一个周期。结果：我们报道了TNFR 2（+）T细胞在AML中的表达增加，并具有向骨髓迁移的高潜能。此外，我们证明了在体内暴露于帕比司他和阿扎胞苷后，患者外周血和骨髓中TNFR 2（+）T细胞水平降低。TNFR 2（+）T细胞的减少与骨髓内效应T细胞产生的干扰素（IFN）-γ和白细胞介素（IL）-2的增加以及有益的临床应答相关。体外机制研究表明，帕比司他作为减少TCLIN.Conclusions的主要驱动因素：我们的研究首次提供了帕比司他与阿扎胞苷联合抑制普遍TNFR 2（+）TCLIN. In的能力的体内验证，从而在AML患者中产生临床益处。(C)2013年AACR。
Purpose: Acute myeloid leukemia (AML) provides an environment that enables immune suppression, resulting in functionally defective effector T cells; regulatory T cells (Treg) are significant contributors to the impaired antitumor immune response. As TNF is present at high levels in AML and TNF receptor-2 (TNFR2)-expressing Tregs identify highly functional Tregs, we examine the hypothesis that TNFR2(+) Tregs are a relevant Treg subset in this cancer. We also determine the effect of the novel combinatorial therapy of the demethylating agent, azacitidine with the histone deacetylase inhibitor, panobinostat on Tregs, particularly TNFR2(+) Tregs.Experimental Design: Thirty healthy donors and 14 patients with AML were enrolled in this study. Patients were treated with azacitidine and panobinostat for 28-day cycles. The frequency and functional relevance of TNFR2(+) Tregs were analyzed subsequently.Results: We report that TNFR2(+) Tregs are increased in AML and have a high migration potential toward the bone marrow. Furthermore, we demonstrate that the level of TNFR2(+) Tregs in the peripheral blood and the bone marrow of patients are decreased in vivo after exposure to panobinostat and azacitidine. Reductions in TNFR2(+) Tregs were associated with increases in Interferon (IFN)-gamma and interleukin (IL)-2 production by effector T cells within the bone marrow and beneficial clinical responses. In vitro mechanistic studies indicated panobinostat as the primary driver for the reduction of Tregs.Conclusions: Our study provides for the first time, in vivo validation of the ability of panobinostat in combination with azacitidine to suppress prevalent TNFR2(+) Tregs, resulting in clinical benefits within patients with AML. (C) 2013 AACR.