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Identification of a Novel Immunogenic HLA-A*0201-Binding Epitope of HER-2/neu with Potent Antitumor Properties¹

Angelos D. Gritzapis^2,*, Ioannis F. Voutsas^*, Eftychia Lekka^*, Nikolaos Tsavaris, Ioannis Missitzis, Panagiota Sotiropoulou, Sonia Perez^*, Michael Papamichail^* and Constantin N. Baxevanis^*

^* Cancer Immunology and Immunotherapy Center and Breast Cancer Clinic, St. Savas Cancer Hospital, Athens, Greece; Pathophysiology Department, Laikon General Hospital and Medical School, National and Kapodistrian University of Athens, Athens, Greece; and Interdisciplinary Research Institute, Universite Libre de Bruxelles, Brussels, Belgium

HER-2/neu oncoprotein is overexpressed in a variety of human tumors and is associated with aggressive disease. Immunogenic HER-2/neu CTL epitopes have been used as vaccines for the treatment of HER-2/neu positive malignancies with limited success. By applying prediction algorithms for MHC class I ligands and proteosomal cleavages, in this study, we describe the identification of HER-2/neu decamer LIAHNQVRQV spanning residues 85–94 (HER-2(10₈₅)). HER-2(10₈₅) proved to bind with high affinity to HLA-A2.1 and was stable for 4 h in an off-kinetics assay. This peptide was immunogenic in HLA-A2.1 transgenic (HHD) mice inducing peptide-specific CTL, which responded to tumor cell lines of various origin coexpressing human HER-2/neu and HLA-A2.1. This demonstrates that HER-2(10₈₅) is naturally processed from endogenous HER-2/neu. Five of sixteen HER-2/neu⁺ HLA-A2.1⁺ breast cancer patients analyzed had HER-2(10₈₅)-reactive T cells ranging from 0.35–0.70% of CD8⁺ T cells. Depletion of T regulatory cells from PBMC enabled the rapid expansion of HLA-A2.1/HER-2(10₈₅)pentamer⁺/CD8⁺ cells (PENT⁺/CD8⁺), whereas significantly lower numbers of CTL could be generated from unfractionated PBMC. HER-2(10₈₅)-specific human CTL recognized the HER-2/neu⁺ HLA-A2.1⁺ tumor cell line SKBR3.A2, as determined by IFN- intracellular staining and in the high sensitivity CD107 degranulation assay. Finally, HER-2(10₈₅) significantly prolonged the survival of HHD mice inoculated with the transplantable ALC.A2.1.HER tumor both in prophylactic and therapeutic settings. These data demonstrate that HER-2(10₈₅) is an immunogenic peptide, capable of eliciting CD8-mediated responses in vitro and in vivo, providing the platform for further exploitation of HER-2(10₈₅) as a possible target for anticancer immunotherapy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the General Secretariat of Research and Technology EPAN YB/3 and PENED 03ED113 (to C.N.B.), and from Regional Operational Program Attika No. 20; MIS code 59605 GR (to M.P.).

² Address correspondence and reprint requests to Dr. Angelos D. Gritzapis, Cancer Immunology and Immunotherapy Center, St. Savas Cancer Hospital, 171 Alexandras Avenue, 11522 Athens, Greece. E-mail address: adgritzapis{at}ciic.gr

³ Abbreviations used in this paper: Treg, T regulatory; MFI, mean fluorescence intensity; PENT, pentamer.