Identification of a highly immunogenic HLA-A*01-binding T cell epitope of WT1

被引:47
作者
Asemissen, Anne Marie
Keilholz, Ulrich
Tenzer, Stefan
Mueller, Margret
Walter, Steffen
Stevanovic, Stefan
Schild, Hansjoerg
Letsch, Anne
Thiel, Eckhard
Rammensee, Hans-Georg
Scheibenbogen, Carmen
机构
[1] Med Klin 3, Charite, D-12200 Berlin, Germany
[2] Johannes Gutenberg Univ Mainz, Inst Immunol, D-6500 Mainz, Germany
[3] Univ Tubingen, Inst Zellbiol, Immunol Abt, Tubingen, Germany
[4] Inst Med Immunol, Charite, Berlin, Germany
关键词
D O I
10.1158/1078-0432.CCR-06-1337
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: The transcription factor Wilms tumor protein 1 (WT1) belongs to a new generation of tumor antigens, as it is essential for tumor cell proliferation and is highly expressed in various hematologic and solid malignancies. The aim of this study was to apply a modified reverse immunology strategy to identify immunogenic epitopes of WT1 which could be useful for immunotherapy. Experimental Design: Potential HLA-A*01 epitopes predicted by a MHC binding algorithm were screened for recognition by peripheral blood mononuclear cells (PBMC) from patients with spontaneous T cell responses using intracellular cytokine cytometry. Epitope processing was shown by proteasomal cleavage. Epitope-specific T cells were generated from CD4+CD25+ regulatory T cell - depleted PBMC. Results: One of five predicted HLA-A*01-binding candidate epitopes showed high immunogenicity as 5 of 14 patients with hematologic malignancies had WT1.317-327-reactiveTcells ranging from 0.4% to 1.5% of CD3+CD8+ T cells. Proteasomal degradation assays indicated the cleavage of WT1.317-327. The depletion of regulatory T cells from PBMCs enabled the rapid expansion of WT1.317-327-specific CTL, whereas no CTL could be generated from unfractionated PBMC. WT1.317-327-specific CTL efficiently lysed an autologous WT1-expressing tumor cell line but not HLA-A*01 - negative WT1-expressing tumor cells. Immunogenicity of the epitope across histologies was verified by the demonstration of spontaneous ex vivo WT1.317-327-specific T cell responses in two of six patients with HLA-A*01 - positive melanoma or lung cancer. Conclusion: In this study, a modified reverse immunology strategy was employed to identify a first immunogenic HLA-A*01 - restricted T cell epitope of the tumor antigen WT1, which is of considerable interest for use in vaccination trials.
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收藏
页码:7476 / 7482
页数:7
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