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* Department of Pathology and
Department of Medical Oncology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands; and
Department of Pathology, Maastricht University, Maastricht, The Netherlands
Based on immune reactivity in response to a whole-cell colon tumor vaccine and using serological identification of Ags by recombinant cDNA expression cloning, we here describe the molecular and functional identification of a novel human tumor Ag. By screening a cDNA expression library derived from the coloncarcinoma cell line HT-29 with pooled colorectal cancer patients’ sera, 26 clones reactive with IgG Abs could be identified. Characterization of these cDNA clones by sequence analysis and alignment, and detailed serological analysis revealed cancer-related immunoreactivity for the ErbB-3-binding protein-1 (Ebp1). Immunohistochemical staining of colorectal tumors and neighboring normal colon tissue indicated the observed cancer-related immunogenicity of Ebp1 to be related to overexpression. Via reverse immunology, five potential HLA-A2-restricted T cell epitopes were identified, of which two (Ebp145–54 and Ebp159–67) bound HLA-A2 with intermediate and high affinity, respectively. Analysis of their immunogenicity in vitro indicated that only the high-affinity Ebp159 epitope gave rise to CD8+ T cells capable of recognizing both exogenously loaded Ebp1 peptide and endogenously expressed Ebp1 on target cells. In addition, in vivo CD8+ T cell responsiveness against the Ebp159 epitope could be detected in two of nine and three of six cancer patients PBMC and tumor draining lymph nodes, respectively, but not in nine of nine healthy donors tested. These data confirm that Ebp1 is an immunogenic protein, capable of eliciting CD8-mediated responses in vivo and in vitro, providing a rationale for further exploration of Ebp1 as a possible target for anticancer immunotherapy.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Dutch Cancer Society Grant 98-1694 (to R.J.B., V.A.S., H.R.H., S.E.H., and R.J.S.).
2 Current address: Dyax S. A., Liege, Belgium.
3 Address correspondence and reprint requests to Prof. Dr. R. J. Scheper, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. E-mail address: rj.scheper{at}vumc.nl
4 Current address: Hasselt University, Diepenbeek, Belgium.
5 V.A.S. and T.D.d.G. share senior authorship.
6 Abbreviations used in this paper: DC, dendritic cell; TAA, tumor-associated Ag; CRC, colorectal cancer; SEREX, serological identification of Ags by cDNA expression cloning; Ebp1, ErbB-3-binding protein-1; ASI, active specific immunotherapy; Tm, tetramer; MoDC, monocyte-derived DC; BrCa, breast cancer; TDLN, tumor-draining lymph node.
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