Back to Search
Start Over
Identification of a highly immunogenic HLA-A*01-binding T cell epitope of WT1.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2006 Dec 15; Vol. 12 (24), pp. 7476-82. - Publication Year :
- 2006
-
Abstract
- 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.<br />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.<br />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-reactive T cells 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.<br />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.
- Subjects :
- Antigens, Neoplasm isolation & purification
Carcinoma immunology
HLA-A1 Antigen
Humans
In Vitro Techniques
Leukemia, Myeloid immunology
Leukocytes immunology
Lung Neoplasms immunology
Lymphocyte Activation physiology
Melanoma immunology
Peptide Fragments immunology
Peptide Fragments metabolism
Proteasome Endopeptidase Complex metabolism
Protein Binding
Skin Neoplasms immunology
T-Lymphocytes, Cytotoxic immunology
WT1 Proteins metabolism
Epitopes, T-Lymphocyte isolation & purification
Epitopes, T-Lymphocyte metabolism
HLA-A Antigens metabolism
WT1 Proteins immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1078-0432
- Volume :
- 12
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 17189421
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-06-1337