Abstract
A potential target for a cancer vaccine would be receptors, such as Tie-2 which are over expressed on tumour endothelium. Using computer aided motif predictions for possible HLA class I epitopes, we have identified peptides from Tie-2 that should bind with a range of affinities to HLA-A*0201. No direct correlation between predicted values and actual binding affinities was observed. Although, the programs did produce a number of false positives, two epitopes were predicted that bound with relatively high affinity when compared with an influenza peptide. We have previously identified a Tie-2 epitope and shown that it was only immunogenic when we substituted preferred amino acids at key anchor residues to increase binding affinity. In this study we used a similar approach to generate modified epitopes. When HLA-A2 transgenic mice were immunised with peptides, CTL killing of the target cells was only achieved when the wild type epitope was presented at moderate levels. Moreover, the efficiency of immunisation was increased when we linked CD4 epitopes to CD8 epitopes. Caution should therefore be employed in the use of both reverse immunology and anchor modification of CTL epitopes in the identification of CTL epitopes for cancer vaccines.
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Aarnoudse CA, van Den Doel PB, Heemskerk B, Schrier PI (1999) Interleukin-2-induced, melanoma-specific T cells recognize CAMEL, an unexpected translation production of LAGE-1. Int J Cancer 82:442–448
Ahlers JD, Takeshita T, Pendleton CD, Berofsky JA (1997) Enhanced immunogenicity of HIV-1 vaccine construct by modification of the native peptide sequence. Proc Natl Acad Sci USA 94:10856–10861
Ahlers JD, Belyakov IM, Thomas EK, Berzofsky J (2001) High affinity T-helper eoitope induces complementary helper APC polarization, increased CTL and protection against viral infection. J Clin Invest 108:1677–1685
Andersen MH, Tan L, Sondergaard I, Zeuthen J, Elliott T, Haurum JS (2000) Poor correspondence between predicted and experimental binding of peptides to class I MHC molecules. Tissue Antigens 55:519–531
Beattie T, JKaul R, Rostron T, Dong T, Easterbrook P, Jaoko W, Kimani J, Plummer F, McMichael A, Rowaland-Jones S (2004) Screening for HIV-specific T-cell responses using overlapping 15-mer peptide pools or optimized epitopes. AIDS 18:1595–1598
Berzofsky JA, Ahlers JD, Belyakov IM (2001) Strategies for designing and optimising new generation vaccines. Nat Rev Immunol 1:209–217
Boel P, Wildmann C, Sensi ML, Brasseur R, Renauld J-C, Coulle P, Boon T, van der Bruggen P (1995) BAGE: a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity 2:167–175
Brichard V, van Pel A, Wolfel T, Wolfel C, de Plaen E, Lethe B, Couile P, Boon T (1993) The tyrosinase gen codes for an antigen recognised by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med 178:489–495
Denkberg G, Klechevsky E, Reiter Y (2002) Modification of a tumor-derived peptide at an HLA-A2 anchor residue can alter the conformation of MHC-peptide comples: probing with TCR-like recombinant antibodies. J Immunol 169:4399–4407
Epstein H, Hardy R, May JS, Johnston MH, Holmes N (1989) Expression and function of HLA-A2.1 in transgenic mice. Eur J Immunol 19:1575–1583
Irvine KR, Parkhurst MR, Shulman EP, Tupesis JP, Custer M, Touloukian CE, Robbins PF, Yafal AG, Greenhalgh P, Sutmuller RP, Offringa R, Rosenberg SA, Restifo NP (1999) Recombinant virus vaccination against “self” antigens using anchor-fixed immunogens. Cancer Res 59:2536–40
Kaipainen A, Vlaykova T, Hatva E, Bohling T, Jekuen A, Pyrhonen S, Alitalo K (1994) Enhanced expression of the tie receptor tyrosine kinase messager RNA in the vascular endothelium of metastatic melanomas. Cancer Res 54:6572–6577
Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Rivoltini L, Topalian SL, Miki T, Rosenberg SA (1994) Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci USA 91:3515–3519
Keogh E, Fikes J, Southwood S, Celis E, Chestnut R, Sette A (2001) Identification of new epitopes from four different tumor-associated antigens: Recognition of naturally processed epitopes correlates with HLA-A*0202- binding affinity. J Immunol 167:787–796
Koga K, Todaka T, Morioko M, Hamada JI, Kai y, Yano S, Okamura A, Takakura N, Suda T, Ushio Y (2001) Expression of angiopoietin-2 in human glioma cells and its role for angiogenesis. Cancer Res 61:6248–6254
Lin P, Polverinin P, Dewhirst M, Shan S, Rao PS, Peters K (1997) Inhibition of tumour angiogenesis using a soluble receptor establishes a role for Tie-2 in pathologic vascular growth. J Clin Invest 100:2072–2078
Maeurer MJ, Martin D, Elder E, Storkus WJ, Lotze MT (1996) Detection of naturally processed and HLA-A1-presented melanoma T-cell epitopes defined by CD8(+) T-cells’ release of granulocyte-macrophage colony-stimulating factor but not by cytolysis. Clin Cancer Res 2:87–95
Milich DR, Hughes JL, McLachlan A, Thornton GB, Moriarty A (1988) Hepatitis B synthetic immunogen comprised of nucleocapsid T-cell sites and an envelope B-cell epitope. Proc Natl Acad Sci USA 85(5):1610–1614
Nakatsuka K, Sugiyama H, Nakagawa Y, Takahashi H (1999) Purification of antigenic peptide from murine hepatoma cells recognized by class-I major histocompatibility complex molecule-restricted cytotoxic T-lymphocytes induced with B7-1-gene-transfected hepatoma cells. J Hepatol 30:119–1129
Nussbaum AK, Kuttler C, Tenzer S, Schild H (2003) Using the world wide web for predicting CTL epitopes. Curr Opin Immunol 15(1):69–74
Okazaki T, Pendleton CD, Lemonnier F, Berzofsky JA (2003) Epitope-enhanced conserved HIV-1 peptide protects HLA-A2-transgenic mice against virus expressing HIV-1 antigen. J Immunol 171:2548–2555
Parker KC, Bednerek MA, Coligan JC (1994) Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual side chains. J Immunol 152:163–175
Peters KG, Coogan A, Berry D, Marks J, Iglehart JD, Kontos CD, Rao P, Trogan E (1998) Expression of Tie-2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis. Brit J cancer 77:51–56
Ramage JM, Metheringham R, Conn A, Spendlove I, Moss RS, Patton DT, Murray JC, Rees RC, Durrant LG (2004) Identification of an HLA-A*0201 cytotoxic T lymphocyte epitope specific to the endothelial antigen Tie-2. Int J Cancer 110:245–250
Rammensee H-G, Bachmann J, Emmerich NN, Bachor OA, Stevanovic S (1999) SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50:213–219
Rodeberg DA, Nuss RA, Heppelmann CJ, Celis E (2005) Lack of effective T-lymphocyte response to the PAX3?FKH3 translocation area in alveolar rhabdomyosarcoma. Cancer Immunol Immunother 54(6):526–534
Rosenberg SA (1999) A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 10:281–287
Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwe P, Marincola FC, Topalian SL, Restifo NP, Dudley ME, Schwarz SL, Spiess PJ, Wunderlich JR, Parkhurst MR, Kawakami Y, Seipp CA, Einhorn JH, White DE (1998) Immunologic and therapeutic evaluation of a sythetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4:321–327
Sarobe P, Pendleton T, Akatsuka T, Lau D, Englehard VH, Feinstone SM, Berofsky JA (1998) Enhanced antigen potency and in vivo immunogenicity of a CTL epitope from hepatitis C virus core protein folllowing amino acid replacement at secondary HLA-A2.1 binding positions. J Clin Invest 102:1239–1248
Sette A, Vitiello A, Reherman B, Fowler P, Nayersina R, Kast WM, Melief CJM, Oseroff C, Yuan L, Ruppert J, Sidney J, del Gurecio M-F, Southwood S, Kubo RT, Chestnut RW, Grey HM, Chisari FV (1994) The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. J Immunol 153:5586–5592
Shirai M, pendleton CD, Ashlers J, Takeshita T, Newman M, Berofsky JA (1994) Helper-cytotoxic T lymphocyt (CTL) determinant linkage required for priming of anti-HIV CD8+ CTL in vivo with peptide vaccine constructs. J Immunol 152:549–556
Takaham M, Tsutsumi M, Tsujiuchi T, Nezu K, Taniguchi S, Kotake Y, Konishi Y (1999) Enhanced expression of Tie-2, its ligand angiopoeitin-1, vascular endothelial groewth factor and CD31 in human non-small cell lung carcinomas. Clin Cancer Res 5:2506–2510
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This article is a symposium paper from the “Robert Baldwin Symposium: 50 years of Cancer Immunotherapy”, held in Nottingham, Great Britain, on 30th June 2005.
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Ramage, J.M., Spendlove, I., Rees, R. et al. The use of reverse immunology to identify HLA-A2 binding epitopes in Tie-2. Cancer Immunol Immunother 55, 1004–1010 (2006). https://doi.org/10.1007/s00262-005-0119-1
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DOI: https://doi.org/10.1007/s00262-005-0119-1