Generation of cytotoxic T cell responses to an HLA-A24 restricted epitope peptide derived from wild-type p53.
Mutations in the p53 gene are the most common genetic alterations found in human tumours, and these mutations result in high levels of p53 protein in the tumour cells. Since the expression levels of wild-type p53 in nonmalignant tissue are usually much lower in contrast, the p53 protein is an attractive target for cancer immunotherapy. We tested p53 encoded HLA-A24 binding peptides for their capacity to elicit anti-tumour cytotoxic T lymphocytes (CTL) in vitro. These peptides were in murine p53-derived cytotoxic peptides, which were being presented to CTL by H-2K(d)and H-2K(b)molecules, because the HLA-A24 peptide binding motifs were similar to the H-2K(d)and H-2K(b). For CTL induction, we used CD8(+)T lymphocytes from the peripheral blood mononuclear cells (PBMC) of healthy donors and the peptides from pulsed dendritic cells as antigen-presenting cells. We identified the peptide, p53-161 (AIYKQSQHM), which was capable of eliciting CTL lines that lysed tumour cells expressing HLA-A24 and p53. The effectors lysed C1RA24 cells (p53(+), HLA-A*2402 transfectant), but not their parental cell lines C1R (p53(+), HLA-A,B null cell). These results strongly indicate that the CTL exerts cytotoxic activity in HLA-A24's restricted manner. The identification of this novel p53 epitope for CTL offers the possibility to design and develop specific immunotherapeutic approaches for treating tumours with p53 mutation in HLA-A24-positive patients.
Umano
Y
Y
Second Department of Surgery, Wakayama Medical School.
Tsunoda
T
T
Tanaka
H
H
Matsuda
K
K
Yamaue
H
H
Tanimura
H
H
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D015234:HLA-A Antigens / Q000276:immunology* / Q000378:metabolism; D059871:HLA-A24 Antigen; D019073:HT29 Cells; D006801:Humans; D020014:K562 Cells; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
D000939:Epitopes; D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D009842:Oligopeptides; D016159:Tumor Suppressor Protein p53