A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma.
A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma.
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DOI：
10.1084/jem.186.5.785
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发表时间：
1997-08-29
期刊：
影响因子：
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通讯作者：
van der Bruggen P
中科院分区：
文献类型：
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作者：
Mandruzzato S;Brasseur F;Andry G;Boon T;van der Bruggen P
在人类肿瘤上被自体溶细胞性 T 淋巴细胞识别的抗原中，迄今为止定义的所有抗原均已在黑色素瘤或肾细胞癌上得到鉴定。我们在此报告了在人口腔鳞状细胞癌上鉴定出一种可被自体溶细胞 T 淋巴细胞识别的抗原。该抗原由 CASP-8 基因的突变形式编码。该基因也称为 FLICE 或 MACH，编码蛋白酶 caspase-8，它是通过 Fas 受体和肿瘤坏死因子受体-1 诱导细胞凋亡所必需的。这种突变在肿瘤细胞中发现，但在患者的正常细胞中没有发现，它修改了终止密码子，并向编码区添加了一个 Alu 重复序列，从而将蛋白质延长了 88 个氨基酸。相对于正常的 caspase-8，改变的蛋白质触发细胞凋亡的能力似乎有所降低。抗原肽是由 HLA-B*3503 呈递的九聚体。最后五个氨基酸是由突变引起的阅读框延伸编码的。这与之前对 CDK4 和 β-连环蛋白突变的观察结果一起表明，产生肿瘤抗原的点突变的很大一部分也在肿瘤转化或进展中发挥作用。
Of the antigens recognized on human tumors by autologous cytolytic T lymphocytes, all those defined thus far have been identified on melanoma or renal cell carcinoma. We report here the identification of an antigen recognized by autologous cytolytic T lymphocytes on a human squamous cell carcinoma of the oral cavity. The antigen is encoded by a mutated form of the CASP-8 gene. This gene, also named FLICE or MACH, codes for protease caspase-8, which is required for induction of apoptosis through the Fas receptor and tumor necrosis factor receptor-1. The mutation, which was found in the tumor cells but not in the normal cells of the patient, modifies the stop codon and adds an Alu repeat to the coding region, thereby lengthening the protein by 88 amino acids. The ability of the altered protein to trigger apoptosis appears to be reduced relative to the normal caspase-8. The antigenic peptide is a nonamer presented by HLA-B*3503. The five last amino acids are encoded by the extension of the reading frame caused by the mutation. This, together with previous observations of CDK4 and β-catenin mutations, suggests that a significant fraction of the point mutations generating a tumor antigen also play a role in the tumoral transformation or progression.