Ripberger Eva, Linnebacher Michael, Schwitalle Yvette, Gebert Johannes, von Knebel Doeberitz Magnus
Institute of Molecular Pathology, Department of Pathology, University of Heidelberg, Heidelberg, Germany.
J Clin Immunol. 2003 Sep;23(5):415-23. doi: 10.1023/a:1025329819121.
Deficient DNA mismatch repair results in microsatellite instability and might induce shifts of translational reading frames of genes encompassing coding microsatellites. These may be translated in truncated proteins, including neo-peptide tails functioning as tumor rejection antigens, when presented in the context of MHC class I. Recently, others and we identified a frameshift mutation in the coding T(10) microsatellite of the O-linked N-acetylglucosamine transferase gene (OGT) occuring in up to 41% of microsatellite unstable colorectal cancers. Here we describe a novel HLA-A0201-restricted cytotoxic T lymphocyte (CTL)-epitope (28-SLYKFSPFPL; FSP06) derived from this mutant OGT-protein. FSP06-specific CTL-clones killed peptide-sensitized target cells and tumor cell lines expressing both HLA-A0201 and mutant OGT proteins. This demonstrates that FSP06 is endogenously expressed and represents a CD8(+)-T cell epitope. Our data corroborate the concept of frameshift peptides constituting a novel subset of tumor-associated antigens specifically encountered in cancer cells with deficient mismatch repair.
DNA错配修复缺陷会导致微卫星不稳定性，并可能导致包含编码微卫星的基因的翻译阅读框发生移位。当在MHC I类的背景下呈现时，这些可能会被翻译成截短的蛋白质，包括作为肿瘤排斥抗原起作用的新肽尾。最近，我们和其他人在O-连接的N-乙酰葡糖胺转移酶基因（OGT）的编码T(10)微卫星中发现了一个移码突变，该突变在高达41%的微卫星不稳定结直肠癌中出现。在这里，我们描述了一种源自这种突变OGT蛋白的新型HLA-A0201限制性细胞毒性T淋巴细胞（CTL）表位（28-SLYKFSPFPL；FSP06）。FSP06特异性CTL克隆杀死了肽致敏的靶细胞以及表达HLA-A0201和突变OGT蛋白的肿瘤细胞系。这表明FSP06是内源性表达的，代表一种CD8(+) - T细胞表位。我们的数据证实了移码肽构成了在错配修复缺陷的癌细胞中特别遇到的肿瘤相关抗原新亚群的概念。
