Generation of CTL recognizing an HLA-A*0201-restricted epitope shared by MAGE-A1, -A2, -A3, -A4, -A6, -A10, and -A12 tumor antigens: implication in a broad-spectrum tumor immunotherapy.
MAGE-A1, -A2, -A3, -A4, -A6, -A10, and -A12 are expressed in a significant proportion of primary and metastatic tumors of various histological types and are targets of tumor Ag-specific CTL. Individual MAGE-A expression varies from one tumor type to the other but, overall, the large majority of tumors expresses at least one MAGE-A Ag. Therefore, targeting epitopes shared by all MAGE-A Ags would be of interest in immunotherapy against a broad spectrum of cancers. In the present study, we describe a heteroclitic MAGE-A peptide (p248V9) that induces CTL in vivo in HLA-A*0201 transgenic HHD mice and in vitro in healthy donors. These CTL are able to recognize two low HLA-A*0201 affinity peptides differing at their C-terminal position and derived from MAGE-A2, -A3, -A4, -A6, -A10, and -A12 (p248G9) and MAGE-A1 (p248D9). Interestingly, p248V9-specific CTL respond to endogenous MAGE-A1, -A2, -A3, -A4, -A6, -A10, and -A12 in an HLA-A*0201-restricted manner and recognize human HLA-A*0201(+)MAGE-A(+) tumor cells of various histological origin. Therefore, this heteroclitic peptide may be considered as a potent candidate for a broad-spectrum tumor vaccination.
Graff-Dubois
Stéphanie
S
Institut National de la Santé et de la Recherche Médicale, Unité 487, Institut Gustave Roussy, Villejuif, France.
Faure
Olivier
O
Gross
David-Alexandre
DA
Alves
Pedro
P
Scardino
Antonio
A
Chouaib
Salem
S
Lemonnier
François A
FA
Kosmatopoulos
Kostas
K
D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015234:HLA-A Antigens / Q000276:immunology / Q000378:metabolism*; D015789:HLA-A2 Antigen; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation; D058950:Melanoma-Specific Antigens; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C119317:MAGE-A10 antigen; C409589:MAGEA12 protein, human; C072013:MAGEA3 protein, human; C095204:MAGEA4 protein, human; C095203:MAGEA6 protein, human; C420909:Mage-a2 antigen; C489519:Mageb3 protein, mouse; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D010446:Peptide Fragments