Kirkin A F, Dzhandzhugazyan K, Zeuthen J
Department of Tumor Cell Biology, Danish Cancer Society, Copenhagen, Denmark.
Exp Clin Immunogenet. 1998;15(1):19-32. doi: 10.1159/000019050.
During the last 6 years significant progress has been achieved in the identification of melanoma-associated antigens recognized by cytotoxic T lymphocytes. These antigens belong the three main groups: tumor-associated testis-specific antigens (MAGE, BAGE, GAGE and PRAME), melanocyte differentiation antigens (tyrosinase, Melan-A/MART-1, gp100, TRP-1 and TRP-2) and mutated or aberrantly expressed antigens (MUM-1, CDK4, beta-catenin, gp100-in4, p15 and N-acetylglucosaminyltransferase V). In this review, we have summarized the available data concerning the characterization of melanoma-associated antigens with focus on their immunogenic and protective properties. The development of a strong immune response against differentiation antigens is limited by the existence of tolerance against these 'self' antigens, permitting the involvement of only T cells with low affinity T cell receptors. Among the melanoma differentiation antigens, only gp100 has been shown to be a tumor regression antigen. The testis-specific antigens such as MAGE and PRAME should potentially be highly immunogenic antigens. They contain several potential HLA class I binding epitopes and are present only in the testes which are not accessible to the cells of the immune system due to the lack of direct contact with the immune cells and the lack of HLA class I expression on the surface of germ cells. But only 2 patients have been found who responded to these antigens in vivo, indicating their genuinely low immunogenicity. A comparison of the predicted secondary structures of these two groups of antigens (testis-specific and differentiation antigens) revealed enrichment of long alpha-helical stretches in the testis-specific antigens. We hypothesize that such highly organized structures could diminish the efficiency of the protein unfolding--a necessary step in the proteolytic cleavage by proteasomes--and, therefore, could be responsible for the low immunogenicity of these proteins. In this case, modifications decreasing the stability of these proteins might be a means to improve the immune response against these potentially therapeutically useful antigens.
在过去6年里，在识别细胞毒性T淋巴细胞所识别的黑色素瘤相关抗原方面取得了重大进展。这些抗原属于三大类：肿瘤相关的睾丸特异性抗原（MAGE、BAGE、GAGE和PRAME）、黑素细胞分化抗原（酪氨酸酶、Melan-A/MART-1、gp100、TRP-1和TRP-2）以及突变或异常表达的抗原（MUM-1、CDK4、β-连环蛋白、gp100-in4、p15和N-乙酰葡糖胺基转移酶V）。在本综述中，我们总结了有关黑色素瘤相关抗原特征的现有数据，重点关注它们的免疫原性和保护特性。针对分化抗原产生强烈免疫反应受到对这些“自身”抗原耐受性的限制，仅允许亲和力低的T细胞受体的T细胞参与。在黑色素瘤分化抗原中，只有gp100已被证明是一种肿瘤消退抗原。睾丸特异性抗原如MAGE和PRAME可能是高度免疫原性的抗原。它们包含几个潜在的HLA I类结合表位，并且仅存在于睾丸中，由于与免疫细胞缺乏直接接触以及生殖细胞表面缺乏HLA I类表达，免疫系统细胞无法接触到这些抗原。但仅发现2例患者在体内对这些抗原产生反应，表明它们的免疫原性确实较低。对这两组抗原（睾丸特异性和分化抗原）预测的二级结构进行比较发现，睾丸特异性抗原中长α-螺旋片段富集。我们推测，这种高度有序的结构可能会降低蛋白质解折叠的效率——这是蛋白酶体进行蛋白水解切割的必要步骤——因此，可能是这些蛋白质免疫原性低的原因。在这种情况下，降低这些蛋白质稳定性的修饰可能是增强针对这些潜在治疗有用抗原的免疫反应的一种手段。
