Abstract
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.
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Kinzler KW, Vogelstein B: Lessons from hereditary colorectal cancer. Cell 87:159–170, 1996
Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen, L, Mecklin JP, Jarvinen H, Powell SM, Jen J, Hamilton SR, Petersen GM, Kinzler KW, Vogelstein B, De la Chapelle A: Clues to the pathogenesis of familial colorectal cancer. Science 260:812–816, 1993
Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava SA: National Cancer Institute Workshop on microsatellite instability for cancer detection and familial predisposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248–5257, 1998
Wang J, Sun L, Myeroff L, Wang X, Gentry LE, Yang J, Liang J, Zborowska E, Markowitz S, Willson JK: Demonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells. J. Biol. Chem. 270:22044–22049, 1995
Shimizu Y, Ikeda S, Fujimori M, Kodama S, Nakahara M, Okajima M, Asahara T: Frequent alterations in the Wnt signaling pathway in colorectal cancer with microsatellite instability. Genes Chromosomes. Cancer, 33:73–81, 2002
Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC, Perucho M: Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 275:967–969, 1997
Lynch HT, Smyrk T: An update on Lynch syndrome. Curr. Opin. Oncol. 10:349–356, 1998
Smyrk TC, Watson P, Kaul K, Lynch HT: Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer 91:2417–2422, 2001
Dolcetti R, Viel A, Doglioni C, Russo A, Guidoboni M, Capozzi E, Vecchiato N, Macri E, Fornasarig M, Boiocchi M: High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am. J. Pathol. 154:1805–1813, 1999.
Townsend A., Ohlen C, Rogers M, Edwards J, Mukherjee S, Bastin J: Source of unique tumour antigens [Letter]. Nature 371:662, 1994
Linnebacher M, Gebert J, Rudy W, Woerner S, Yuan YP, Bork P, von Knebel Doeberitz M: Frameshift peptide-derived T-cell epitopes: A source of novel tumor-specific antigens. Int. J Cancer 93:6–11, 2001
Saeterdal I, Bjorheim J, Lislerud K, Gjertsen MK, Bukholm IK, Olsen OC, Nesland JM, Eriksen JA, Moller M, Lindblom A, Gaudernack G: Frameshift-mutation-derived peptides as tumorspecific antigens in inherited and spontaneous colorectal cancer. Proc. Natl. Acad. Sci. U.S.A 98:13255–13260, 2001
Saeterdal I, Gjertsen MK, Straten P, Eriksen JA, Gaudernack G: A TGF betaRII frameshift-mutation-derived CTL epitope recognised by HLA-A2–restricted CD8+ T cells. Cancer Immunol Immunother. 50:469–476, 2001
Kim NG, Rhee H, Li LS, Kim H, Lee JS, Kim JH, Kim NK, Kim H: Identification of MARCKS, FLJ11383 and TAF1B as putative novel target genes in colorectal carcinomas with microsatellite instability. Oncogene 21:5081–5087, 2002
Duval A, Reperant M, Compoint A, Seruca R, Ranzani GN, Iacopetta B, Hamelin R: Target gene mutation profile differs between gastrointestinal and endometrial tumors with mismatch repair deficiency. Cancer Res. 62:1609–1612, 2002
Woerner SM, Gebert J, Yuan YP, Sutter C, Ridder R, Bork P, von Knebel Doeberitz M: Systematic identification of genes with coding microsatellites mutated in DNA mismatch repair-deficient cancer cells. Int. J Cancer 93:12–19, 2001
Lubas WA, Frank DW, Krause M, Hanover JA: O-Linked GlcNAc transferase is a conserved nucleocytoplasmic protein containing tetratricopeptide repeats. J. Biol. Chem. 272:9316–9324, 1997
Wells L, Vosseller K, Hart GW: Glycosylation of nucleocytoplasmic proteins: Signal transduction and O-GlcNAc. Science 291:2376–2378, 2001
Comer FI, Hart GW: O-Glycosylation of nuclear and cytosolic proteins. Dynamic interplay between O-GlcNAc and O-phosphate. J. Biol. Chem. 275:29179–29182, 2000
Schultze JL, Michalak S, Seamon MJ, Dranoff G, Jung K, Daley J, Delgado JC, Gribben JG, Nadler LM: CD40–activated human B cells: An alternative source of highly efficient antigen presenting cells to generate autologous antigen-specific T cells for adoptive immunotherapy. J. Clin. Invest 100:2757–2765, 1997
Brossart P, Bevan MJ: Selective activation of Fas/Fas ligandmediated cytotoxicity by a self peptide. J. Exp. Med. 183:2449–2458, 1996
Houbiers JG, Nijman HW, van der Burg, SH., Drijfhout JW, Kenemans P, van de Velde CJ, Brand A, Momburg F, Kast WM, Melief CJ: In vitro induction of human cytotoxic T lymphocyte responses against peptides of mutant and wild-type p53. Eur. J. Immunol. 23:2072–2077, 1993
Deuschle U, Pepperkok R, Wang FB, Giordano TJ, McAllister WT, Ansorge W, Bujard H: Regulated expression of foreign genes in mammalian cells under the control of coliphage T3 RNA polymerase and lac repressor. Proc. Natl. Acad. Sci. USA 86:5400–5404, 1989
Morel S, Levy F, Burlet-Schiltz O, Brasseur F, Probst-Kepper M, Peitrequin AL, Monsarrat B, Van Velthoven R, Cerottini JC, Boon T, Gairin JE, Van den Eynde BJ: Processing of some antigens by the standard proteasome but not by the immunoproteasome results in poor presentation by dendritic cells. Immunity. 12:107–117, 2000
Akiyama Y, Tsubouchi N, Yuasa Y: Frequent somatic mutations of hMSH3 with reference to microsatellite instability in hereditary nonpolyposis colorectal cancers. Biochem. Biophys. Res. Commun. 236:248–252, 1997
Bustin SA, Li SR, Phillips S, Dorudi S: Expression of HLA class II in colorectal cancer: Evidence for enhanced immunogenicity of microsatellite-instability-positive tumours. Tumour. Biol. 22:294–298, 2001
Andersen SN, Rognum TO, Lund E, Meling GI, Hauge S: Strong HLA-DR expression in large bowel carcinomas is associated with good prognosis. Br. J. Cancer 68:80–85, 1993
Wright CM, Dent OF, Barker M, Newland RC, Chapuis PH, Bokey EL, Young JP, Leggett BA, Jass JR, Macdonald G: A. Prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer. Br. J. Surg. 87:1197–1202, 2000
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Ripberger, E., Linnebacher, M., Schwitalle, Y. et al. Identification of an HLA-A0201-Restricted CTL Epitope Generated by a Tumor-Specific Frameshift Mutation in a Coding Microsatellite of the OGT Gene. J Clin Immunol 23, 415–423 (2003). https://doi.org/10.1023/A:1025329819121
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DOI: https://doi.org/10.1023/A:1025329819121