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.