The shared tumor associated antigen cyclin-A2 is recognized by high-avidity T-cells.
Cyclin-A2, a key cell cycle regulator, has been shown to be overexpressed in various types of malignancies with little expression in normal tissue. Such tumor-associated genes potentially are useful targets for cancer immunotherapy. However, high-avidity cyclin-specific T cells are considered to be thymically deleted. We identified at least one nonameric HLA-A*0201 binding cyclin-A2 epitope by a reverse immunology approach. Using a highly efficient T-cell expansion system that is based on CD40-activated B (CD40-B) cells as sole antigen-presenting cells we successfully generated cyclin-A2 specific CTL from HLA-A*0201(+) donors. Interestingly, high-avidity cyclin-A2 specific CTL lines, which recognized peptide-pulsed and antigen expressing target cells, were indeed generated by stimulation with CD40-B cells when pulsed with low concentrations of peptide, whereas CD40-B cells pulsed at saturating concentrations could only induce low-avidity CTL, which recognized peptide-pulsed target cells only. One high-avidity CTL line was subcloned and CTL clones, whose peptide concentration required for half-maximal lysis were less than 1 nM, could lyse cyclin-A2 expressing tumor cells. Taken together, cyclin A2 is an attractive candidate for immune intervention in a significant number of cancer patients and high-avidity T cells can be readily generated using CD40-B cells as antigen-presenting cells.
Kondo
Eisei
E
Max Eder Junior Research Group, Clinic I for Internal Medicine, University Hospital of Cologne, Cologne, Germany.
Maecker
Britta
B
Draube
Andreas
A
Klein-Gonzalez
Nela
N
Shimabukuro-Vornhagen
Alexander
A
Schultze
Joachim L
JL
von Bergwelt-Baildon
Michael S
MS
D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D019925:Cyclin A / Q000276:immunology* / Q000378:metabolism; D056751:Cyclin A2; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D015234:HLA-A Antigens / Q000276:immunology* / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; C503721:CCNA2 protein, human; D019013:CD40 Antigens; D019925:Cyclin A; D056751:Cyclin A2; D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D007371:Interferon-gamma