The DNA demethylating agent 5-aza-2'-deoxycytidine activates NY-ESO-1 antigenicity in orthotopic human glioma
The DNA demethylating agent 5-aza-2'-deoxycytidine activates NY-ESO-1 antigenicity in orthotopic human glioma
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DOI：
10.1002/ijc.23407
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发表时间：
2008-06-01
影响因子：
6.4
通讯作者：
Yoshida, Jun
中科院分区：
文献类型：
--
作者：
Natsume, Atsushi;Wakabayashi, Toshihiko;Yoshida, Jun
肿瘤/睾丸抗原（cta）被认为是人类恶性肿瘤免疫治疗的合适靶点。已经证明，在多种肿瘤中，某些cta的表达通过其启动子CpG岛的去甲基化被激活。在我们的研究中，我们已经表明，虽然13种CTA在30个人类胶质瘤标本和来自日本人群的新建立的细胞系中的复合表达几乎是不可见的，但dna去甲基化剂5-aza-2'-.脱氧胞苷（5-aza-CdR）在胶质瘤细胞中显著地重新激活了CTA的表达，而在正常的人类细胞中却没有。我们使用一种新的酶切测序（TM）技术和甲基化特异性PCR，量化了5-aza-CdR治疗后ny - eso -1（最具免疫原性的cas之一）甲基化状态的降低。微阵列分析显示，5-aza-CdR能够向免疫系统发出信号，特别是人类白细胞抗原（HLA） I类上调。cr -51释放细胞毒性试验和NY-ESO-1特异性细胞毒性T淋巴细胞（CTL）的冷靶抑制试验表明，细胞表面出现了新生的NY-ESO-1抗原肽。在原位异种移植模型中，系统给药5-aza-CdR导致移植肿瘤的体积显著减少，并延长了ny - eso -1特异性ctl的动物存活时间。这些结果表明，5-aza- cdr诱导了低免疫原性胶质瘤中表观遗传沉默cta的表达，从而为靶向5-aza-的肿瘤免疫治疗提供了一种新的策略。CdR-induced cta。(C) 2008 Wiley-Liss, Inc。
Cancer/testis antigens (CTAs) are considered to be suitable targets for the immunotherapy of human malignancies. It has been demonstrated that in a variety of tumors, the expression of certain CTAs is activated via the demethylation of their promoter CpG islands. In our study, we have shown that while the composite expression of 13 CTAs in 30 human glioma specimens and newly established cell lines from the Japanese population was nearly imperceptible, the DNA-demethylating agent 5-aza-2'-.deoxycytidine (5-aza-CdR) markedly reactivated CTA expression in glioma cells but not in normal human cells. We quantified the diminished methylation status of NY-ESO-1-one of the most immunogenic CTAs-following 5-aza-CdR treatment by using a novel Pyrose-quencing (TM) technology and methylation-specific PCR. Microarray analysis revealed that 5-aza-CdR is capable of signaling the immune system, particularly, human leukocyte antigen (HLA) class I upregulation. Cr-51-release cytotoxicity assays and cold target inhibition assays using NY-ESO-1 -specific cytotoxic T lymphocyte (CTL) lines demonstrated the presentation of de novo NY-ESO-1 antigenic peptides on the cell surfaces. In an orthotopic xenograft model, the systemic administration of 5-aza-CdR resulted in a significant volume reduction of the transplanted tumors and prolonged the survival of the animals after the adoptive transfer of NY-ESO-1-specitic CTLs. These results suggested that 5-aza-CdR induces the expression of epigenetically silenced CTAs in poorly immunogenic gliomas and thereby presents a new strategy for tumor immunotherapy targeting 5-aza-.CdR-induced CTAs. (C) 2008 Wiley-Liss, Inc.