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Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens

Item Type:Article
Title:Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens
Creators Name:Linnebacher, M. and Gebert, J. and Rudy, W. and Woerner, S. and Yuan, Y.P. and von Knebel-Doeberitz, M.
Abstract:Microsatellite instability (MSI) caused by defective DNA mismatch repair (MMR) is a hallmark of hereditary nonpolyposis colorectal cancers (HNPCC) but also occurs in about 15% of sporadic tumors. If instability affects microsatellites in coding regions, translational frameshifts lead to truncated proteins often marked by unique frameshift peptide sequences at their C-terminus. Since MSI tumors show enhanced lymphocytic infiltration and our previous analysis identified numerous coding mono- and dinucleotide repeat-bearing candidate genes as targets of genetic instability, we examined the role of frameshift peptides in triggering cellular immune responses. Using peptide pulsed autologous CD40-activated B cells, we have generated cytotoxic T lymphocytes (CTL) that specifically recognize HLA-A2. I-restricted peptides derived from frameshift sequences. Among 16 frameshift peptides predicted from mutations in 8 different genes, 3 peptides conferred specific lysis of target cells exogenously loaded with cognate peptide. One peptide derived from a (-I) frameshift mutation in the TGFβIIR gene gave rise to a CTL bulk culture capable of lysing the MSI colorectal cancer cell line HCTII6 carrying this frameshift mutation. Given the huge number of human coding microsatellites and assuming only a fraction being mutated and encoding immunologically relevant peptides in MSI tumors, frameshift protein sequences represent a novel subclass of tumor-specific antigens. It is tempting to speculate that a frameshift peptide-directed vaccination approach not only could offer new treatment modalities for existing MSI tumors but also might benefit asymptomatic at-risk individuals in HNPCC families by a prophylactic vaccination strategy.
Keywords:DNA Mismatch Repair, Frameshift Peptides, Microsatellite Instability, T-cell Epitopes, Tumor Antigens
Source:International Journal of Cancer
Page Range:6-11
Date:1 January 2001
Official Publication:https://doi.org/10.1002/ijc.1298
PubMed:View item in PubMed

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