title: EphA2 as target of anticancer immunotherapy: identification of HLA-A*0201-restricted epitopes.
abstract: EphA2 (Eck) is a tyrosine kinase receptor that is overexpressed in several human cancers such as breast, colon, lung, prostate, gastric carcinoma, and metastatic melanoma but not in nonmalignant counterparts. To validate EphA2 as a tumor antigen recognized by CD8+ T lymphocytes, we used reverse immunology approach to identify HLA-A*0201-restricted epitopes. Peptides bearing the HLA-A*0201-specific anchor motifs were analyzed for their capacity to bind and stabilize the HLA-A*0201 molecules. Two peptides, EphA2(58) and EphA2(550), with a high affinity for HLA-A*0201 were selected. Both peptides were immunogenic in the HLA-A*0201-transgenic HHD mice. Interestingly, peptide-specific murine CTLs cell lines responded to COS-7 cells coexpressing HLA-A*0201 and EphA2 and to EphA2-positive human tumor cells of various origin (renal cell, lung, and colon carcinoma and sarcoma). This demonstrates that EphA2(58) and EphA2(550) are naturally processed from endogenous EphA2. In addition, EphA2(58) and EphA2(550) stimulated specific CD8(+) T cells from healthy donor peripheral blood mononuclear cells. These T cells recognized EphA2-positive human tumor cells in an HLA-A*0201-restricted manner. Interestingly, EphA2-specific CD8+ T cells were detected in the peripheral blood mononuclear cells of prostate cancer patients. These results show for the first time that EphA2 is a tumor rejection antigen and lead us to propose EphA2(58) and EphA2(550) peptides for a broad-spectrum-tumor immunotherapy.
authors.affiliation: INSERM487, Institut Gustave Roussy, Villejuif. Unité d'Immunité Cellulaire Antivirale, Institut Pasteur, Paris. Immuno-Designed Molecules, Paris, France.
authors.forename: Pedro M S
authors.initials: PM
authors.lastname: Alves
authors.forename: Olivier
authors.initials: O
authors.lastname: Faure
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Graff-Dubois
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Gross
authors.forename: Sébastien
authors.initials: S
authors.lastname: Cornet
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
authors.forename: Isabelle
authors.initials: I
authors.lastname: Miconnet
authors.forename: François A
authors.initials: FA
authors.lastname: Lemonnier
authors.forename: Kostas
authors.initials: K
authors.lastname: Kosmatopoulos
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015234:HLA-A Antigens / Q000276:immunology*; D015789:HLA-A2 Antigen; D007167:Immunotherapy / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D036104:Receptor, EphA2 / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D036104:Receptor, EphA2