HDAC11 plays an essential role in regulating OX40 ligand expression in Hodgkin lymphoma
HDAC11 plays an essential role in regulating OX40 ligand expression in Hodgkin lymphoma
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DOI：
10.1182/blood-2010-08-303701
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发表时间：
2011-03-10
期刊：
影响因子：
20.3
通讯作者：
Younes, Anas
中科院分区：
文献类型：
--
作者：
Buglio, Daniela;Khaskhely, Noor M.;Younes, Anas
在霍奇金淋巴瘤(HL)中，恶性细胞被大量反应性浸润性炎症细胞包围，包括表达OX40的T细胞和产生白介素10(IL-10)的调节性T细胞(T-reg)。这些T-reg细胞可以抑制免疫反应，从而有助于维持免疫耐受和抗肿瘤反应不足。OX40L与OX40受体的结合对于抗原特异性记忆T细胞的产生和宿主抗肿瘤免疫的诱导是必不可少的。在本研究中，我们研究了组蛋白脱乙酰酶抑制剂(HDACis)是否可以通过调节HL细胞中OX40L的表达来诱导良好的抗肿瘤免疫反应。我们发现HDAC以剂量依赖的方式上调HL细胞株OX40L表面的表达。选择性抑制HDAC11表达、显著上调OX40L和诱导HL细胞凋亡的小干扰RNA(SiRNAs)和沉默HDAC11转录本可增加HL细胞培养上清液中肿瘤坏死因子-α(TNF-α)和IL-17的产生。此外，HDACi诱导的OX40L抑制产生IL-10的1型T-reg细胞。这些结果首次证明HDAC11在调节OX40L的表达中起着重要作用。药物抑制HDAC11可能在HL患者中产生良好的抗肿瘤免疫反应。(血。2011；117(10)：2910-2917)
In Hodgkin lymphoma (HL), the malignant cells are surrounded by a large number of reactive infiltrating inflammatory cells, including OX40-expressing T cells and interleukin 10 (IL-10)-producing regulatory T (T-reg) cells. These T-reg cells can suppress the immune response and thus contribute to the maintenance of immune tolerance and to insufficient antitumor response. The engagement of OX40L with the OX40 receptor is essential for the generation of antigen-specific memory T cells and for the induction of host anti-tumor immunity. In the present study, we investigated whether histone deacetylase inhibitors (HDACis) may induce a favorable antitumor immune response by regulating the expression of OX40L in HL. We found that HDACis up-regulated OX40L surface expression in HL cell lines in a dose-dependent manner. Small interfering RNAs (siRNAs) that selectively inhibited HDAC11 expression, significantly up-regulated OX40L and induced apoptosis in HL cell lines, and silencing HDAC11 transcripts increased the production of tumor necrosis-alpha (TNF-alpha) and IL-17 in the supernatants of HL cells. Furthermore, HDACI-induced OX40L inhibited the generation of IL-10-producing type 1 T-reg cells. These results demonstrate for the first time that HDAC11 plays an essential role in regulating OX40L expression. Pharmacologic inhibition of HDAC11 may produce a favorable antitumor immune response in patients with HL. (Blood. 2011;117(10):2910-2917)