Cheever M A, Chen W, Disis M L, Takahashi M, Peace D J
Division of Medical Oncology, University of Washington, Seattle 98195.
Ann N Y Acad Sci. 1993 Aug 12;690:101-12. doi: 10.1111/j.1749-6632.1993.tb44000.x.
The process of malignant transformation can be ascribed to a series of characteristics and definable mutations of genes which encode proteins that control cell growth and differentiation. During the course of malignant transformation the cancer-related genes are altered by a variety of mechanisms including translocations, deletions, and point mutations which commonly result in the expression of aberrant proteins. Our laboratory has focused on determining the extent to which cancer-specific proteins expressed by aberrant cancer-related genes can function as tumor-specific antigens. The current paper reviews our studies with two prototype cancer-specific proteins, mutated p21ras protein and chimeric p210bcr-abl protein. Ras protooncogenes are activated by point mutation in approximately 20% of human malignancies. The mutations occur primarily at codons 12 or 61 and result in the expression of p21ras proteins with single substituted amino acids. Only a limited number of amino acid substitutions occur. Murine studies demonstrate that immunization with synthetic peptides corresponding to the mutated segment can elicit both class II restricted CD4+ helper/inducer T-cell responses and class I restricted CD8+ cytotoxic T-cell responses specific for mutated p21ras protein. In addition, the existence in vivo of tumors expressing mutated ras proteins can be detected by assaying for T-cell immunity to the mutated segment of ras protein. Preliminary human studies show that some patients with colon cancer have existent antibody responses to p21ras protein, implying the possible existence of autochthonous T-cell immunity to mutated ras proteins in those patients. In chronic myelogenous leukemia the human c-abl protooncogene from chromosome 9 is translocated to the specific breakpoint cluster (bcr) region on chromosome 22. The translocation results in the formation of a bcr-abl fusion gene that encodes at 210-kD chimeric protein. The joining region segment of chimeric bcr-abl protein is composed of a unique combination of c-abl and bcr amino acids and is expressed only by malignant cells. Studies demonstrate that immunization of mice with synthetic peptides corresponding to the joining region segment can elicit class II restricted CD4+ T-cell responses to p210bcr-abl proteins. Preliminary studies show that bcr-abl peptides can bind in the groove of both murine and human class I MHC molecules and can elicit bcr-abl peptide-specific cytotoxic T lymphocytes (CTL). Whether bcr-abl peptide-specific CTL can lyse cells expressing bcr-abl protein is a yet unknown. In summary, the results of the studies reviewed confirm that cancer-specific oncogenic proteins can serve as tumor-specific antigens.
恶性转化过程可归因于一系列特征以及编码控制细胞生长和分化蛋白质的基因的可定义突变。在恶性转化过程中，与癌症相关的基因通过多种机制发生改变，包括易位、缺失和点突变，这些通常会导致异常蛋白质的表达。我们实验室专注于确定由异常的癌症相关基因表达的癌症特异性蛋白质在多大程度上可作为肿瘤特异性抗原。本文回顾了我们对两种原型癌症特异性蛋白质——突变型p21ras蛋白和嵌合型p210bcr-abl蛋白的研究。Ras原癌基因在约20%的人类恶性肿瘤中通过点突变被激活。这些突变主要发生在密码子12或61处，导致表达具有单个取代氨基酸的p21ras蛋白。仅发生有限数量的氨基酸取代。小鼠研究表明，用对应于突变片段的合成肽进行免疫可引发针对突变型p21ras蛋白的II类限制性CD4+辅助/诱导性T细胞反应和I类限制性CD8+细胞毒性T细胞反应。此外，通过检测对ras蛋白突变片段的T细胞免疫，可以检测体内表达突变型ras蛋白的肿瘤的存在。初步人体研究表明，一些结肠癌患者对p21ras蛋白存在抗体反应，这意味着这些患者可能存在对突变型ras蛋白的自身T细胞免疫。在慢性粒细胞白血病中，来自9号染色体的人类c-abl原癌基因易位至22号染色体上的特定断裂点簇（bcr）区域。这种易位导致形成一个bcr-abl融合基因，该基因编码一种210-kD的嵌合蛋白。嵌合型bcr-abl蛋白的连接区域片段由c-abl和bcr氨基酸的独特组合组成，且仅由恶性细胞表达。研究表明，用对应于连接区域片段的合成肽对小鼠进行免疫可引发针对p210bcr-abl蛋白的II类限制性CD4+ T细胞反应。初步研究表明，bcr-abl肽可结合在小鼠和人类I类MHC分子的凹槽中，并可引发bcr-abl肽特异性细胞毒性T淋巴细胞（CTL）。bcr-abl肽特异性CTL是否能裂解表达bcr-abl蛋白的细胞尚不清楚。总之，所回顾研究的结果证实，癌症特异性致癌蛋白可作为肿瘤特异性抗原。
