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Multidrug Resistance-associated Protein 3 Is a Tumor Rejection Antigen Recognized by HLA-A2402-restricted Cytotoxic T Lymphocytes¹

Cancer Vaccine Development Division, Kurume University Research Center for Innovative Cancer Therapy [A. Y., K. K., M. K., T. M., K. I.], and Department of Immunology, Kurume University School of Medicine [A. Y., K. I.], Kurume 830-0011, Japan

The identification of tumor rejection antigens recognized by CTLs and its application in peptide-based specific immunotherapy against melanomas have been extensively investigated in the past decade. However, only a small number of studies regarding these issues in other epithelial cancers have been reported. In this study, we show that a multidrug resistance-associated protein 3 (MRP3) is a tumor rejection antigen recognized by HLA-A2402-restricted CTLs established from T cells infiltrating into lung adenocarcinoma. MRP3 is expressed in differing quantities in tumor cells of various tissue types and origins. Four dominant MRP3-derived antigenic peptides that are recognized by the CTLs have been identified, each possessing in vitro immunogenicity. Namely, these four peptides (MRP3–503, MRP3–692, MRP3–765, and MRP3–1293) can induce peptide-specific CTLs after in vitro stimulation with these peptides in peripheral blood mononuclear cell cultures of HLA-A24⁺ cancer patients, with the CTLs expressing cytotoxicity against HLA-A2402⁺ MRP3⁺ tumor cells but not against either HLA-A2402^- or MRP3^- target cells. The peptide specificity of the cytotoxicity of the CTLs was further confirmed by using peptide-loaded HLA-A24⁺ EBV-transformed B cells. Widespread MRP3 expression in various tumor cell lines and tumor tissues at the mRNA level was confirmed. Furthermore, reactivities of the MRP3-peptide-induced CTLs against tumor cells correlated with MRP3 expression in the tumor cells. These results suggest that MRP3 and its derived peptides described in the present paper are potential candidates for cancer vaccines in regard to HLA-A24⁺ patients with various tumors, particularly for those tumors that show anticancer drug resistance.

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