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Enhanced induction of human WT1-specific cytotoxic T lymphocytes with a 9-mer WT1 peptide modified at HLA-A*2402-binding residues
- Source :
- Cancer Immunology, Immunotherapy. 51:614-620
- Publication Year :
- 2002
- Publisher :
- Springer Science and Business Media LLC, 2002.
-
Abstract
- The Wilms' tumor gene WT1 is overexpressed in most types of leukemias and various kinds of solid tumors, including lung and breast cancer, and participates in leukemogenesis and tumorigenesis. WT1 protein has been reported to be a promising tumor antigen in mouse and human. In the present study, a single amino-acid substitution, M-->Y, was introduced into the first anchor motif at position 2 of the natural immunogenic HLA-A*2402-restricted 9-mer WT1 peptide (CMTWNQMNL; a.a. 235-243). This substitution increased the binding affinity of the 9-mer WT1 peptide to HLA-A*2402 molecules from 1.82 x 10(-5) to 6.40 x 10(-7) M. As expected from the increased binding affinity, the modified 9-mer WT1 peptide (CYTWNQMNL) elicited WT1-specific cytotoxic T lymphocytes (CTL) more effectively than the natural 9-mer WT1 peptide from peripheral blood mononuclear cells (PBMC) of HLA-A*2402-positive healthy volunteers. CTL induced by the modified 9-mer WT1 peptide killed the natural 9-mer WT1 peptide-pulsed CIR-A*2402 cells, primary leukemia cells with endogenous WT1 expression and lung cancer cell lines in a WT1-specific HLA-A*2402-restricted manner. These results showed that this modified 9-mer WT1 peptide was more immunogenic for the induction of WT1-specific CTL than the natural 9-mer WT1 peptide, and that CTL induced by the modified 9-mer WT1 peptide could effectively recognize and kill tumor cells with endogenous WT1 expression. Therefore, cancer immunotherapy using this modified 9-mer WT1 peptide should provide efficacious treatment for HLA-A*2402-positive patients with leukemias and solid tumors.
- Subjects :
- congenital, hereditary, and neonatal diseases and abnormalities
Cancer Research
medicine.medical_treatment
Immunology
Peptide
Biology
urologic and male genital diseases
medicine.disease_cause
Epitope
Cancer immunotherapy
Neoplasms
Tumor Cells, Cultured
medicine
Humans
Immunology and Allergy
Cytotoxic T cell
WT1 Proteins
chemistry.chemical_classification
HLA-A Antigens
urogenital system
fungi
Immunotherapy
Peptide Fragments
female genital diseases and pregnancy complications
Tumor antigen
CTL
Oncology
chemistry
Cancer research
Carcinogenesis
T-Lymphocytes, Cytotoxic
Subjects
Details
- ISSN :
- 14320851 and 03407004
- Volume :
- 51
- Database :
- OpenAIRE
- Journal :
- Cancer Immunology, Immunotherapy
- Accession number :
- edsair.doi.dedup.....8949708b132f409a1249a72c9d7aab58