title: Heterogeneous T-cell response to MAGE-A10(254-262): high avidity-specific cytolytic T lymphocytes show superior antitumor activity.
abstract: MAGE-encoded antigens, which are expressed by tumors of many histological types but not in normal tissues, are suitable candidates for vaccine-based immunotherapy of cancers. Thus far, however, T-cell responses to MAGE antigens have been detected only occasionally in cancer patients. In contrast, by using HLA/peptide fluorescent tetramers, we have observed recently that CD8(+) T cells specific for peptide MAGE-A10(254-262) can be detected frequently in peptide-stimulated peripheral blood mononuclear cells from HLA-A2-expressing melanoma patients and healthy donors. On the basis of these results, antitumoral vaccination trials using peptide MAGE-A10(254-262) have been implemented recently. In the present study, we have characterized MAGE-A10(254-262)-specific CD8(+) T cells in polyclonal cultures and at the clonal level. The results indicate that the repertoire of MAGE-A10(254-262)-specific CD8(+) T cells is diverse both in terms of clonal composition, efficiency of peptide recognition, and tumor-specific lytic activity. Importantly, only CD8(+) T cells able to recognize the antigenic peptide with high efficiency are able to lyse MAGE-A10-expressing tumor cells. Under defined experimental conditions, the tetramer staining intensity exhibited by MAGE-A10(254-262)-specific CD8(+) T cells correlates with efficiency of peptide recognition so that "high" and "low" avidity cells can be separated by FACS. Altogether, the data reported here provide evidence for functional diversity of MAGE-A10(254-262)-specific T cells and will be instrumental for the monitoring of peptide MAGE-A10(254-262)-based clinical trials.
authors.affiliation: Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Centre Hospitalier Universitaire Vaudois, Avenue Pierre-Decker, 1011 Lausanne, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Dutoit
authors.forename: V
authors.initials: V
authors.lastname: Rubio-Godoy
authors.forename: P Y
authors.initials: PY
authors.lastname: Dietrich
authors.forename: A L
authors.initials: AL
authors.lastname: Quiqueres
authors.forename: V
authors.initials: V
authors.lastname: Schnuriger
authors.forename: D
authors.initials: D
authors.lastname: Rimoldi
authors.forename: D
authors.initials: D
authors.lastname: Liénard
authors.forename: D
authors.initials: D
authors.lastname: Speiser
authors.forename: P
authors.initials: P
authors.lastname: Guillaume
authors.forename: P
authors.initials: P
authors.lastname: Batard
authors.forename: J C
authors.initials: JC
authors.lastname: Cerottini
authors.forename: P
authors.initials: P
authors.lastname: Romero
authors.forename: D
authors.initials: D
authors.lastname: Valmori
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D000912:Antibodies, Neoplasm / Q000276:immunology; D000915:Antibody Affinity / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D008545:Melanoma / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; C119317:MAGE-A10 antigen; D009363:Neoplasm Proteins; D010446:Peptide Fragments