Identification of a new HLA-A(*)0201-restricted T-cell epitope from the tyrosinase-related protein 2 (TRP2) melanoma antigen.
For the development of peptide-based immunotherapies, the identification of additional tumor antigens and T-cell epitopes is required. Because HLA-A(*)0201 is the most common allele in Caucasians, who represent the majority of patients with melanomas, 6 peptides carrying an HLA-A(*)0201 motif were synthesized from tyrosinase-related protein-2 (TRP2) melanoma antigen and tested for binding affinity to the HLA allele using processing-defective T2 cells. These peptides were then pulsed onto autologous dendritic cells and used to stimulate in vitro CD8(+)-enriched T cells isolated from peripheral blood of HLA-A(*)02(+) healthy donors or melanoma patients for the induction of specific cytotoxic T lymphocytes (CTLs). One peptide, TRP2(288-296) (SLDDYNHLV), the best HLA-A(*)0201 binder, elicited specific CTLs from 1 of 4 patients and 3 of 4 healthy donors. The induced CTLs from the patient and from 1 donor efficiently recognized HLA-A(*)02(+) TRP2(+) melanomas as well as COS-7 cells expressing HLA-A(*)0201 and TRP2 in an HLA class I-restricted manner, as assessed by cytokine production and direct cytolysis. The remaining 2 CTL lines derived from 2 donors displayed low T-cell receptor avidity, which could lyse melanoma cells in the presence of exogenous peptide. Since TRP2 is an antigen expressed in most melanomas, identification of the TRP2/HLA-A(*)0201 peptide SLDDYNHLV may facilitate the design of present peptide-based immunotherapies for the treatment of a large fraction of melanoma patients.
Sun
Y
Y
Clinical Cooperation Unit for Dermato-Oncology (DKFZ), Heidelberg, Germany.
Song
M
M
Stevanović
S
S
Jankowiak
C
C
Paschen
A
A
Rammensee
H G
HG
Schadendorf
D
D
D020816:Amino Acid Motifs / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology*; D019556:COS Cells; D003713:Dendritic Cells / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000737:chemistry / Q000276:immunology*; D008213:Lymphocyte Activation; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D009363:Neoplasm Proteins / Q000737:chemistry / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology
D000951:Antigens, Neoplasm; D000939:Epitopes; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase