Complete loss of HLA class I antigen expression on melanoma cells:: A result of successive mutational events
Complete loss of HLA class I antigen expression on melanoma cells:: A result of successive mutational events
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DOI：
10.1002/ijc.10906
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发表时间：
2003-03-01
影响因子：
6.4
通讯作者：
Schadendorf, D
中科院分区：
文献类型：
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作者：
Paschen, A;Méndez, RM;Schadendorf, D
HLA I类分子表面表达的改变已被描述为肿瘤逃避细胞毒性T细胞识别的策略。我们检测到1例黑色素瘤患者的2种肿瘤细胞系的HLA I类抗原呈递完全丧失，第一种起源于与原发性肿瘤同时诊断的区域淋巴结病变，第二种建立于8个月后的转移性胸腔积液样本。抗原呈递不能用IFN-γ诱导，但用b2 m cDNA转染肿瘤细胞后可以恢复，表明b2 m表达缺陷。对这种缺陷的性质的分析表明，它起源于至少2个影响b2 m基因的两个拷贝的突变事件：一个b2 m基因中498 bp的微缺失，包括其整个外显子1，以及涉及第二个b2 m基因的整个拷贝的宏缺失。微卫星分析表明IS染色体长臂（q）上的几个特异性标记存在洛缺失，从而指出了该基因的大缺失。FISH证实了15 q的结构失衡。FISH研究还表明染色体15 q的结构异常变体与2条明显完整的染色体15 q共存，该染色体15 q携带纯合b2 m微缺失。阻断肿瘤细胞中b2 m的表达为癌症患者的免疫治疗建立了障碍，其早期发生应是免疫治疗策略开发和设计的主要考虑因素。(C)2002 Wiley-Liss，Inc.
Alterations in the surface expression of HLA class I molecules have been described as a strategy of tumors to evade recognition by cytotoxic T cells. We detected complete loss of HLA class I antigen presentation for 2 tumor cell lines from 1 melanoma patient, the first originated from a regional lymph node lesion diagnosed simultaneously with the primary tumor and the second established 8 months later from a metastatic pleural effusion sample. Antigen presentation was not inducible with IFN-gamma but could be restored after transfection of tumor cells with b2m cDNA, indicating a defect in b2m expression. Analysis of the nature of this defect revealed that it originated from at least 2 mutational events affecting both copies of the b2m gene: a microdeletion of 498 bp in one b2m gene, including its entire exon 1, and a macrodeletion involving the entire copy of the second b2m gene. Microsatellite analysis pointed to the macrodeletion by demonstrating LOH for several specific markers on the long arm (q) of chromosome IS. Structural imbalance of 15q was verified by FISH. FISH studies also indicated the coexistence of a structurally abnormal variant of chromosome 15q with 2 apparently entire chromosomes 15q harboring the homozygous b2m microdeletion. Block of b2m expression in tumor cells builds a barrier to immunotherapy of cancer patients, and its early incidence should be of major consideration in the development and design of immunotherapeutic strategies. (C) 2002 Wiley-Liss, Inc.