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Frameshift peptide‐derived T‐cell epitopes: A source of novel tumor‐specific antigens
Author(s) -
Linnebacher Michael,
Gebert Johannes,
Rudy Wolfgang,
Woerner Stefan,
Yuan Yan P.,
Bork Peer,
von Knebel Doeberitz Magnus
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.1298
Subject(s) - frameshift mutation , biology , microsatellite instability , ctl* , epitope , dna mismatch repair , microbiology and biotechnology , genetics , gene , cancer research , antigen , mutation , dna repair , cd8 , microsatellite , allele
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‐A2.1‐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 (−1) frameshift mutation in the TGFβIIR gene gave rise to a CTL bulk culture capable of lysing the MSI colorectal cancer cell line HCT116 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. © 2001 Wiley‐Liss, Inc.