Frequent loss of HLA-A2 expression in metastasizing ovarian carcinomas associated with genomic haplotype loss and HLA-A2-restricted HER-2/neu-specific immunity
Frequent loss of HLA-A2 expression in metastasizing ovarian carcinomas associated with genomic haplotype loss and HLA-A2-restricted HER-2/neu-specific immunity
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DOI：
10.1158/0008-5472.can-06-0029
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Kiessling, Rolf
中科院分区：
文献类型：
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作者：
Norell, Hakan;Carlsten, Mattias;Kiessling, Rolf
HLA I 类分子的缺陷表达在肿瘤细胞中很常见，可能会逃避 CTL 介导的免疫。我们在此研究卵巢癌患者中 HLA I 类表达的变化及其潜在的分子机制。采用流式细胞术检测12例卵巢癌患者未培养的肿瘤细胞中HLA I类和HLA-A2的表达水平。在转移性癌细胞中进行抗原加工机制 (APM) 成分的分子分析，并确定这些细胞和原发性肿瘤中的 HLA 基因型。通过酶联免疫斑点测定评估 HER-2/neu 特异性免疫。所有患者的转移性肿瘤细胞均表达低水平的 HLA I 类表面抗原。在 9 名 HLA-A2(+) 患者中，有 6 名患者的 HLA-A2 表达存在异质性，其中一个肿瘤细胞亚群表现出 HLA-A2 表达减少或缺失。一种源自患者的肿瘤细胞系完全缺乏 HLA-A2，但表现出 APM 成分的组成型表达和 HLA I 类高表达，这种表达可通过 IFN-γ 治疗进一步诱导。基因分型显示转移性肿瘤细胞中单倍型丢失，而从原发性肿瘤显微解剖的肿瘤组织则显示出完整的 HLA 基因复合物。有趣的是，该患者的淋巴细胞中 HLA-A2 限制的 HER-2/neu 特异性 T 细胞反应很明显。 HLA I 类抗原表达异常是卵巢癌进展过程中的常见特征，单倍型丢失首次被描述为潜在机制。
Defective expression of HLA class I molecules is common in tumor cells and may allow escape from CTL-mediated immunity. We here investigate alterations in expression of HLA class I and their underlying molecular mechanisms in ovarian cancer patients. The HLA class I and HLA-A2 expression levels on noncultured tumor cells of 12 patients diagnosed with ovarian carcinoma were investigated by flow cytometry. Molecular analyses of antigen-processing machinery (APM) components were done in metastatic cancer cells, and the HLA genotype was determined in both these and the primary tumor. HER-2/neu-specific immunity was evaluated by enzyme-linked immunospot assays. The metastatic tumor cells from all patients expressed low levels of HLA class I surface antigens. In six of nine HLA-A2(+) patients, HLA-A2 expression was heterogeneous with a subpopulation of tumor cells exhibiting decreased or absent HLA-A2 expression. One patient-derived tumor cell line completely lacked HLA-A2 but exhibited constitutive expression of APM components and high HLA class I expression that was further inducible by IFN-gamma treatment. Genotyping showed a haplotype loss in the metastatic tumor cells, whereas tumor tissue microdissected from the primary tumor exhibited an intact HLA gene complex. Interestingly, HLA-A2-restricted HER-2/neu-specific T-cell responses were evident among the lymphocytes of this patient. Abnormalities in HLA class I antigen expression are common features during the progression of ovarian cancer, and haplotype loss was, for the first time, described as an underlying mechanism.