Giorda Ezio, Sibilio Leonardo, Martayan Aline, Moretti Sara, Venturo Irene, Mottolese Marcella, Ferrara Giovan Battista, Cappellacci Sandra, Eibenschutz Laura, Catricalà Caterina, Grammatico Paola, Giacomini Patrizio
Laboratory of Immunology, Regina Elena Cancer Institute CRS, 00158 Rome, Italy.
Cancer Res. 2003 Jul 15;63(14):4119-27.
The ultimate outcome of an immune response (escape or surveillance) depends on a delicate balance of opposing signals delivered by activating and inhibitory immune receptors expressed by cytotoxic T lymphocytes and natural killer cells. In this light, loss and down-regulation of human leukocyte antigens (HLA) class I molecules, while important for keeping tumors below the T-cell detection levels, may incite recognition of missing self. Conversely, the maintenance of normal levels of expression (or even up-regulation) may be favorable to tumors, at least in certain cases. In this study, we took advantage of a previously characterized panel of 15 early passage tumor cell lines (mainly from melanoma and lung carcinoma lesions) enriched with class I-low phenotypes. These cells were systematically characterized by Northern and/or Western blotting (e.g., mini-transcriptome/mini-proteome analysis) for the expression of HLA-A, -B, -C, beta(2)-microglobulin, and the members of the "antigen processing machinery" of class I molecules (LMP2, LMP7, TAP1, TAP2, tapasin, calreticulin, calnexin, and ERp57). In addition, we established four pairs of cultures, each comprising melanoma cells and normal melanocytes from the same patient. We found that approximately 97% of the 185 tested gene products are expressed (although often weakly), and in many cases coordinately regulated in 18 of 19 tumor cell lines. Linked expression patterns could be hierarchically arranged by statistical methods and graphically described as a class I HLA "coordinome." Deviations (both down- and up-regulation) from the coordinome expression pattern inherited from the normal, paired melanocyte counterpart, were allowed but limited in magnitude, as if melanoma cells were trying to keep a "low profile" HLA phenotype. We conclude that irreversible HLA loss is a rare event, and class I expression in tumor cells almost invariably results from reversible gene regulatory (rather than gene disruption) events.
免疫反应的最终结果（逃逸或监测）取决于细胞毒性T淋巴细胞和自然杀伤细胞表达的激活和抑制性免疫受体所传递的相反信号之间的微妙平衡。据此，人类白细胞抗原（HLA）I类分子的缺失和下调虽然对于使肿瘤处于T细胞检测水平以下很重要，但可能会引发对缺失自我的识别。相反，维持正常表达水平（甚至上调）可能对肿瘤有利，至少在某些情况下如此。在本研究中，我们利用了一组先前表征的15种早期传代肿瘤细胞系（主要来自黑色素瘤和肺癌病变），这些细胞系富含I类低表型。通过Northern和/或Western印迹法（例如，微转录组/微蛋白质组分析）系统地表征这些细胞中HLA-A、-B、-C、β2-微球蛋白以及I类分子“抗原加工机制”成员（LMP2、LMP7、TAP1、TAP2、塔帕辛、钙网蛋白、钙连蛋白和ERp57）的表达。此外，我们建立了四对培养物，每对均由来自同一患者的黑色素瘤细胞和正常黑色素细胞组成。我们发现，在185个测试的基因产物中，约97%有表达（尽管通常较弱），并且在19个肿瘤细胞系中的18个中，许多情况下是协同调节的。通过统计方法可以将相关的表达模式进行层次排列，并以图形方式描述为I类HLA“协调组”。与从正常配对的黑色素细胞对应物继承的协调组表达模式相比，允许出现偏差（下调和上调），但幅度有限，就好像黑色素瘤细胞试图保持一种“HLA低表型”。我们得出结论，不可逆的HLA缺失是一种罕见事件，肿瘤细胞中的I类表达几乎总是由可逆的基因调控（而非基因破坏）事件导致的。
