Peptide epitopes from the Wilms' tumor 1 oncoprotein stimulate CD4+ and CD8+ T cells that recognize and kill human malignant mesothelioma tumor cells
| Autor: | Rong H. Zhang, Tatyana Korontsvit, Javier Pinilla-Ibarz, Peter Maslak, David A. Scheinberg, Tao Dao, Rena J. May, Victoriya Zakhaleva |
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| Rok vydání: | 2007 |
| Předmět: |
CD4-Positive T-Lymphocytes
Chromium Mesothelioma Cancer Research medicine.medical_treatment T-Lymphocytes Biology CD8-Positive T-Lymphocytes Epitope Epitopes Interferon-gamma medicine Tumor Cells Cultured Cytotoxic T cell Humans WT1 Proteins Transcription factor Cell Proliferation Leukemia Reverse Transcriptase Polymerase Chain Reaction fungi Wilms' tumor Immunotherapy T lymphocyte Dendritic Cells HLA-DR Antigens medicine.disease Peptide Fragments Oncology Cancer research Immunization CD8 HLA-DRB1 Chains T-Lymphocytes Cytotoxic |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 13(15 Pt 1) |
| ISSN: | 1078-0432 |
| Popis: | Purpose: Wilms' tumor 1 protein (WT1), a transcription factor overexpressed in malignant mesothelioma, leukemias, and other solid tumors, is an ideal target for immunotherapy. WT1 class I peptide epitopes that were identified and shown to stimulate CD8+ T cells are being tested as vaccine candidates in several clinical trials. The induction and maintenance of a robust memory CD8+ cytotoxic T-cell response requires CD4+ T-cell help.Experimental Design: Three HLA class II peptide epitopes of WT1 with high predictive affinities to multiple HLA-DRB1 molecules were identified using the SYFPEITHI algorithm. Due to the highly polymorphic nature of the HLA class II alleles, such reactivity is critical in the development of a broadly useful therapeutic. One of the WT1 CD4+ peptide epitopes, 122-140, comprises a previously identified CD8+ peptide epitope (126-134). By mutating residue 126 from an arginine to a tyrosine, we embedded a synthetic immunogenic analogue CD8+ epitope (126-134) inside the longer peptide (122-140). This analogue was previously designed to improve immunogenicity and induce a potent CD8+ response.Results: WT1 peptides 328-349 and 423-441 are able to stimulate a peptide-specific CD4+ response that can recognize WT1+ tumor cells in multiple HLA-DRB1 settings as determined by IFN-γ enzyme-linked immunospot assays. The mutated WT1 peptide epitope 122-140 is able to induce CD4+ and cytotoxic CD8+ WT1-specific T-cell responses that can recognize the native WT1 epitopes on the surface of human WT1+ cancer cells. Cross-priming experiments showed that antigen-presenting cells pulsed with either mesothelioma or leukemia tumor lysates can process and present each of the CD4+ peptides identified.Conclusions: These studies provide the rationale for using the WT1 CD4+ peptides in conjunction with CD8+ peptide epitopes to vaccinate patients with WT1-expressing cancers. |
| Databáze: | OpenAIRE |
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