An HLA-A24-restricted cytotoxic T lymphocyte epitope of a tumor-associated protein, survivin.
To date an increasing number of T-cell epitopes derived from various tumor-associated antigens have been reported, and they proved to play significant roles for tumor rejection both in vivo and in vitro. Survivin was originally identified as a member of the inhibitor of apoptosis protein family. Expression of this gene is developmentally regulated. Although survivin is expressed during normal fetal development, the expression is barely detected in terminally differentiated adult tissues except for testis, thymus, and placenta. In contrast, it is abundantly expressed in a wide variety of malignant tissues. We examined the expression of survivin and the two splicing variants survivin-2B and survivin-DeltaEx3 in various cancer cells, immortalized cells, and normal adult tissues. It was demonstrated that two splicing variants were detected in various types of cancer cells as well as survivin, and their expression was more restricted to cancer cells as compared with survivin expression. To identify HLA-A24-restricted T-cell epitopes from survivin and the variant proteins, three peptides were selected from amino acid sequence of these proteins, based on the HLA-A24-binding motif. Peptide binding assay to HLA-A24 revealed that only one peptide designated as survivin-2B80-88 (AYACNTSTL) was capable of binding to HLA-A24. By stimulating peripheral blood lymphocytes with the peptide-pulsed antigen-presenting cells, CTLs were successfully induced in vitro from five of five HLA-A24-positive cancer patients. The CTLs showed significant cytotoxicity against HLA-A24-positive survivin-2B-positive cancer cells. These data suggest that survivin-2B80-88 may be a potent T-cell epitope eliciting CTL response against a splicing variant survivin-2B, which is specifically expressed in many kinds of cancer cells.
Hirohashi
Yoshihiko
Y
Department of Pathology, Sapporo Medical University School of Medicine, South-1 West-17, Chuo-ku Sapporo 060-8543, Japan.
Torigoe
Toshihiko
T
Maeda
Akiko
A
Nabeta
Yuki
Y
Kamiguchi
Kenjiro
K
Sato
Takashi
T
Yoda
Junichi
J
Ikeda
Hideyuki
H
Hirata
Kouichi
K
Yamanaka
Noboru
N
Sato
Noriyuki
N
D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells; D000951:Antigens, Neoplasm / Q000276:immunology*; D002857:Chromium / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D017931:DNA Primers / Q000737:chemistry; D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015234:HLA-A Antigens / Q000276:immunology*; D059871:HLA-A24 Antigen; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D009369:Neoplasms / Q000235:genetics / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D019154:Protein Splicing / Q000276:immunology; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000276:immunology
D000951:Antigens, Neoplasm; C107489:BIRC5 protein, human; D017931:DNA Primers; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D000077022:Survivin; D002857:Chromium; D012313:RNA