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EphA2 as Target of Anticancer Immunotherapy

Identification of HLA-A*0201-Restricted Epitopes

¹ INSERM487, Institut Gustave Roussy, Villejuif;
² Unité d’Immunité Cellulaire Antivirale, Institut Pasteur, Paris; and
³ Immuno-Designed Molecules, Paris, France

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, EphA2₅₈ and EphA2₅₅₀, 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 EphA2₅₈ and EphA2₅₅₀ are naturally processed from endogenous EphA2. In addition, EphA2₅₈ and EphA2₅₅₀ 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 EphA2₅₈ and EphA2₅₅₀ peptides for a broad-spectrum-tumor immunotherapy.

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