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Multidrug resistance-associated protein 3 is a tumor rejection antigen recognized by HLA-A2402-restricted cytotoxic T
1Cancer Vaccine Development Division, Kurume University Research Center for Innovative Cancer Therapy, Kurume 830-0011, Japan. akiymd@med.kurume-u.ac.jp
Abstract:
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.
Insights
Multidrug resistance-associated protein 3 (MRP3) acts as a tumor rejection antigen in lung adenocarcinoma. Researchers identified four MRP3-derived peptides that can stimulate cancer-fighting T cells, offering potential for new cancer vaccines in HLA-A24(+) patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Research on tumor rejection antigens for specific immunotherapy has primarily focused on melanomas, with limited investigation in other epithelial cancers.
- Cytotoxic T lymphocytes (CTLs) play a crucial role in tumor rejection, recognizing specific antigens presented on cancer cells.
Purpose of the Study:
- To identify novel tumor rejection antigens in epithelial cancers beyond melanoma.
- To investigate the potential of multidrug resistance-associated protein 3 (MRP3) as a target for T cell-based immunotherapy.
- To characterize MRP3-derived peptides for their immunogenicity and potential use in cancer vaccines.
Main Methods:
- Establishment of CTLs recognizing tumor antigens from lung adenocarcinoma infiltrating T cells.
- Identification and characterization of antigenic peptides derived from MRP3.
- In vitro stimulation of peripheral blood mononuclear cells (PBMCs) from HLA-A24(+) cancer patients with identified peptides.
- Assessment of CTL cytotoxicity against tumor cells with varying HLA-A2402 and MRP3 expression levels.
- Confirmation of peptide specificity using peptide-loaded EBV-transformed B cells.
- Analysis of MRP3 expression at the mRNA level in various tumor cell lines and tissues.
Main Results:
- Multidrug resistance-associated protein 3 (MRP3) was identified as a tumor rejection antigen recognized by HLA-A2402-restricted CTLs in lung adenocarcinoma.
- Four dominant MRP3-derived antigenic peptides (MRP3-503, MRP3-692, MRP3-765, and MRP3-1293) were identified with in vitro immunogenicity.
- These peptides induced peptide-specific CTLs in HLA-A24(+) cancer patients' PBMCs, which exhibited cytotoxicity against HLA-A2402(+) MRP3(+) tumor cells.
- CTL reactivity correlated with MRP3 expression in tumor cells, and cytotoxicity was specific to HLA-A2402 and MRP3 positive targets.
- Widespread MRP3 expression was confirmed at the mRNA level across diverse tumor cell lines and tissues.
Conclusions:
- MRP3 functions as a tumor rejection antigen in lung adenocarcinoma and is recognized by HLA-A2402-restricted CTLs.
- The identified MRP3-derived peptides are immunogenic and can induce tumor-specific CTL responses in HLA-A24(+) cancer patients.
- MRP3 and its derived peptides represent promising candidates for developing peptide-based cancer vaccines for HLA-A24(+) patients, particularly those with drug-resistant tumors.
