title: Lack of tumor recognition by cytolytic T lymphocyte clones recognizing peptide 195-203 encoded by gene MAGE-A3 and presented by HLA-A24 molecules.
abstract: Gene MAGE-A3 encodes tumor-specific antigenic peptides recognized by T cells on many tumors. MAGE-A3 peptides presented by HLA class I molecules have been identified using CD8 lymphocytes stimulated with cells that either expressed gene MAGE-A3 or were pulsed with candidate peptides. One antigen identified with the latter method is peptide MAGE-A3(195-203) IMPKAGLLI, presented by HLA-A24 molecules. It has been used to vaccinate advanced cancer patients. Here, we have used HLA/peptide tetramers to detect T cells recognizing this peptide. Their frequency was estimated to be 2 x 10(-8) of the blood CD8 cells in non-cancerous HLA-A24(+) individuals, which is tenfold lower than the reported frequencies of T cells against other MAGE peptides. In the blood of a patient vaccinated with MAGE-A3, the estimated frequency was 5 x 10(-7). Anti-MAGE-3.A24 cytolytic T cell clones were derived, that lysed peptide-pulsed cells with half-maximal effect at the low concentration of 500 pM. However, these CTL did not recognize a panel of HLA-A24(+) tumor cells that expressed MAGE-A3 at levels similar to those found in HLA-A1(+) tumor cells recognized by anti-MAGE-3.A1 CTLs. Furthermore, 293-EBNA cells transfected with MAGE-A3 and HLA-A24 constructs were hardly recognized by the anti-MAGE-3.A24 CTL clones. These results suggest that peptide MAGE-A3(195-203) is poorly processed and is not an appropriate target for cancer immunotherapy.
authors.affiliation: Christian de Duve Institute of Cellular Pathology, Université catholique de Louvain, Avenue Hippocrate 74, UCL 7459, 1200 Brussels, Belgium.
authors.forename: Tomoko
authors.initials: T
authors.lastname: So
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hanagiri
authors.forename: Jacques
authors.initials: J
authors.lastname: Chapiro
authors.forename: Didier
authors.initials: D
authors.lastname: Colau
authors.forename: Francis
authors.initials: F
authors.lastname: Brasseur
authors.forename: Kosei
authors.initials: K
authors.lastname: Yasumoto
authors.forename: Thierry
authors.initials: T
authors.lastname: Boon
authors.forename: Pierre G
authors.initials: PG
authors.lastname: Coulie
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D002999:Clone Cells; D015234:HLA-A Antigens / Q000276:immunology; D059871:HLA-A24 Antigen; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008545:Melanoma / Q000276:immunology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D010455:Peptides / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D010455:Peptides