Expression of HLA class I antigens and restoration of antigen-specific ctl response in melanoma cells following 5-aza-2′-deoxycytidine treatment
Expression of HLA class I antigens and restoration of antigen-specific ctl response in melanoma cells following 5-aza-2′-deoxycytidine treatment
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DOI：
10.1002/ijc.1452
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发表时间：
2001-10-15
影响因子：
6.4
通讯作者：
Garrido, F
中科院分区：
文献类型：
--
作者：
Serrano, A;Tanzarella, S;Garrido, F
肿瘤细胞上HLA I类/肽复合物的细胞表面表达是产生基于T细胞的免疫应答的关键步骤。一些遗传缺陷的基础上缺乏HLA I类表达的特点。在这里，我们描述了另一种分子机制，占完全缺乏HLA I类分子表达的肿瘤细胞系（MSR 3-mel）来自黑色素瘤患者。鉴定了MSR 3-mel DNA的超甲基化，特别是HLA-A和-B基因的超甲基化，其导致HLA I类重链转录的丢失。用去甲基化剂5 '-氮杂-2'-脱氧胞苷（DAC）处理MSR 3-mel细胞允许HLA-A和-B转录，恢复HLA I类抗原的细胞表面表达和MAGE特异性细胞毒性T淋巴细胞对肿瘤细胞的识别。MSR 3-mel系获自接受基于法师-3. AI T细胞的肽免疫疗法的无应答患者的转移性病变。很容易推测，高甲基化诱导的HLA I类表达的缺乏是对疫苗接种的应答受损的原因。这项研究提供了人类肿瘤细胞使用DNA超甲基化来关闭HLA I类基因的第一个证据，从而提供了一种逃避免疫识别的新途径。(C)2001 Wiley-Liss，Inc.
Cell surface expression of HLA class I/peptide complexes on tumor cells is a key step in the generation of T-cell-based immune responses. Several genetic defects underlying the lack of HLA class I expression have been characterized. Here we describe another molecular mechanism that accounts for the complete absence of HLA class I molecule expression in a tumor line (MSR3-mel) derived from a melanoma patient. Hypermethylation of the MSR3-mel DNA, specifically of HLA-A and -B genes, was identified, which resulted in loss of HLA class I heavy chain transcription. Treatment of MSR3-mel cells with the demethylating agent 5'-aza-2'-deoxycytidine (DAC) allowed HLA-A and -B transcription, restoring cell surface expression of HLA class I antigens and tumor cell recognition by MAGE-specific cytotoxic T lymphocytes. The MSR3-mel line was obtained from a metastatic lesion of a nonresponding patient undergoing MAGE-3.AI T-cell-based peptide immunotherapy. It is tempting to speculate that the hypermethylation-induced lack of HLA class I expression is the cause of the impaired response to vaccination. This study provides the first evidence that DNA hypermethylation is used by human neoplastic cells to switch off HLA class I genes, thus providing a new route of escape from immune recognition. (C) 2001 Wiley-Liss, Inc.