Mapping of novel peptides of WT-1 and presenting HLA alleles that induce epitope-specific HLA-restricted T cells with cytotoxic activity against WT-1+ leukemias

• Published in: Blood Vol. 120; no. 8; pp. 1633 - 1646
• Main Authors: Doubrovina, Ekaterina, Carpenter, Taissia, Pankov, Dmitry, Selvakumar, Annamalai, Hasan, Aisha, O'Reilly, Richard J.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 23-08-2012; Americain Society of Hematology; American Society of Hematology
• Subjects: Alleles; Amino Acid Sequence; Biological and medical sciences; Cell Line, Tumor; Epitope Mapping; Epitopes, T-Lymphocyte - immunology; Hematologic and hematopoietic diseases; HLA Antigens - genetics; HLA Antigens - immunology; Humans; Immunobiology; Leukemia - genetics; Leukemia - immunology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Molecular Sequence Data; Peptides - chemistry; Peptides - immunology; T-Lymphocytes - immunology; T-Lymphocytes, Cytotoxic - immunology; Tumor Cells, Cultured; WT1 Proteins - chemistry; WT1 Proteins - immunology; Cartography; HLA-System; Antigenic determinant; Hematology; Peptides; Leukemia; Major histocompatibility system; Malignant hemopathy; Biological activity; Allele; Histocompatibility restriction; Genetics; Cytotoxic T lymphocyte; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-11-394619

The Wilms tumor protein (WT-1) is widely recognized as a tumor antigen that is expressed differentially by several malignancies. However, WT-1 peptides known to induce tumoricidal T cells are few. In the present study, we evaluated T-cell responses of 56 healthy donors to in vitro sensitization with autologous APCs loaded with a pool of overlapping 15-mer peptides spanning the sequence of WT-1. Thereafter, we mapped the WT-1 peptides eliciting responses in each individual, defined the immunogenic peptides, and identified their presenting HLA alleles. We report 41 previously unreported epitopes of WT-1: 5 presented by class II and 36 by class I alleles, including 10 that could be presented by more than 1 class I allele. IFNγ+ T cells responding to 98% of the class I and 60% of the class II epitopes exhibited HLA-restricted cytotoxicity against peptide-loaded targets. T cells specific for 36 WT-1 peptides were evaluable for leukemocidal activity, of which 27 (75%) lysed WT-1+ leukemic targets sharing their restricting HLA allele. Each epitope identified induced T-cell responses in most donors sharing the epitopes' presenting allele; these responses often exceeded responses to flanking peptides predicted to be more immunogenic. This series of immunogenic epitopes of WT-1 should prove useful for immunotherapies targeting WT-1+ malignancies.