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Accepted: April 16, 2003
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 Nacetylglucosamine 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 peptidesensitized target cells and tumor cell lines expressing both HLAA0201 and mutant OGT proteins. This demonstrates that FSP06 is endogenously expressed and represents aCD8C-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.
KEY WORDS: Microsatellite instability; frameshift peptides; tumor antigens; DNA mismatch repair; T-cell epitopes.
Abbreviations used: cMS, coding microsatellite; FSP, frameshift peptide; MSI, microsatellite instability;MSS,micosatellite stability;MMR, mismatch repair; OGT, O-linked N-acetylglucosamine transferase; OGT(FS), OGT containing a ([degrees]1) frameshift mutation; TAA, tumor associated antigen; TGFbetaRII, transforming growth factor beta receptor type II.
INTRODUCTION
Microsatellite instability (MSI) due to DNA mismatch repair( MMR)deficiency is observed in colorectal adenomas and carcinomas from individuals with hereditary nonpolyposis colorectal cancer (HNPCC) (1, 2) but also occurs in sporadic tumors (3). MSI causes length variations at short repetitive DNA stretches, called microsatellites. If MSI affects coding microsatellites, C-terminally truncated proteins will be generated, often comprising neo-peptide tails. These truncated gene products are believed to have an impaired function and might thereby contribute to MSIdriven carcinogenesis. In line with this hypothesis, several genes known to play important roles in colorectal carcinogenesis as for example transforming growth factor beta receptor type II (TGFbetaRII), Bax and TCF-4 are targets of this mechanism (4-6).
Following proteasomal degradation, parts of these novel proteins might be presented as immunogenic neo-peptides at the surface of MSIC cancer cells in the context of MHC-class I molecules, thereby allowing for recognition of frameshift-derived nonself by effector cells of the immune system. The enhanced lymphocytic infiltration and Crohn's like reaction observed in MSIC tumors could be due to the presence of...