HLA class I phenotype and genotype alterations in cervical carcinomas and derivative cell lines
HLA class I phenotype and genotype alterations in cervical carcinomas and derivative cell lines
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DOI：
10.1111/j.1399-0039.1998.tb03005.x
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发表时间：
1998-06-01
期刊：
影响因子：
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通讯作者：
Fleuren, GJ
中科院分区：
文献类型：
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作者：
Koopman, LA;Mulder, A;Fleuren, GJ
人类白细胞抗原I类分子表达下调是肿瘤生物学中的常见事件。在不同的肿瘤中已经定义了各种潜在的机制，但对宫颈癌中的人类白细胞抗原缺失机制的了解有限。为了确定表面表达缺失的原因，我们对5个原发子宫颈肿瘤及其衍生细胞系进行了详细的人类白细胞抗原I类表型和基因分型研究。免疫组织化学和流式细胞术分别用一组广泛的等位基因特异性单抗评估原代组织和细胞系上的蛋白表达。3例表达缺失，包括B15基因座缺失、B15等位基因缺失、A74/B15单倍型和另一单倍型A24等位基因缺失。细胞因子治疗诱导了B15基因位点丢失的重新表达，提示该肿瘤缺乏结构性表达的调节缺陷。相反，DNA和/或RNA水平的分子分析显示，另一种非诱导性丢失与染色体上的人类白细胞抗原基因缺陷有关。进行杂合性缺失分析以确认较大的基因组缺失。本研究表明，人类白细胞抗原基因突变或杂合性缺失以及调控缺陷参与了宫颈癌的发生。由此导致的KLA表达的变化可能直接影响对这些人乳头瘤病毒相关肿瘤的免疫反应的有效性。潜在丢失机制的异质性可能为个体肿瘤提供各种逃脱免疫监视的机会，并可能严重影响基于T细胞的治疗。
Downregulation of HLA class I expression is a common event in tumor biology. Various underlying mechanisms have been defined in different tumors, but the knowledge of HLA loss mechanisms in cervical carcinoma is limited. To identify causalities for loss of surface expression, we performed a detailed investigation of HLA class I phenotypes and genotypes in 5 primary cervical tumors and on derivative cell lines. Protein ex pression on primary tissues and cell lines was evaluated by immunohistochemistry and flow cytometry respectively, using a broad panel of allele-specific monoclonal antibodies. Loss of expression was seen in 3 cases, comprising B15-locus loss, B15-allelic loss, and loss of an A74/B15 haplotype and an A24 allele of the other haplotype. Cytokine treatment induced reexpression of the B15-locus loss, suggesting a regulatory defect underlying lack of constitutive expression in this tumor. In contrast, molecular analyses at the DNA and/or RNA level showed that the other, non-inducible, losses were associated with chromosomal HLA gene defects. Loss of heterozygosity analysis was performed to confirm larger genomic deletions. This study shows that HLA gene defects by mutation or loss of heterozygosity as well as regulatory defects are involved in cervical carcinogenesis. The resulting changes in KLA expression may directly affect the efficacy of the immune response to these human papillomavirus-related neoplasms. Heterogeneity in the underlying loss mechanisms may offer individual tumors various opportunities to escape immune surveillance, and may severely compromise T-cell based therapy.