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Cell Mol Immunol. 2018 Aug;15(8):768-781. doi: 10.1038/cmi.2017.155. Epub 2018 Jan 29.

A modified HLA-A*0201-restricted CTL epitope from human oncoprotein (hPEBP4) induces more efficient antitumor responses.

Sun W1,2,3, Shi J4, Wu J2,3, Zhang J5, Chen H1, Li Y6, Liu S1, Wu Y1, Tian Z7, Cao X1,2,3,8, Li N9.

Author information

1
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, 200433, China.
2
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
3
Biotherapy Center, The Affiliated Central Hospital of Qingdao University, Qingdao, 266042, China.
4
Department of Surgery, Changhai Hospital, Shanghai, 200433, China.
5
Department of Surgery, Changzheng Hospital, Shanghai, 200003, China.
6
Shanghai Center for Bioinformation Technology, Shanghai, 201203, China.
7
Institute of Immunology, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China.
8
National Key Laboratory of Medical Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, Beijing, 100005, China.
9
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, 200433, China. linan@immunol.org.

Abstract

We previously identified human phosphatidylethanolamine-binding protein 4 (hPEBP4) as an antiapoptotic protein with increased expression levels in breast, ovarian and prostate cancer cells, but low expression levels in normal tissues, which makes hPEBP4 an attractive target for immunotherapy. Here, we developed hPEBP4-derived immunogenic peptides for inducing antigen-specific cytotoxic T lymphocytes (CTLs) targeting breast cancer. A panel of hPEBP4-derived peptides predicted by peptide-MHC-binding algorithms was evaluated to characterize their HLA-A2.1 affinity and immunogenicity. We identified a novel immunogenic peptide, P40-48 (TLFCQGLEV), that was capable of eliciting specific CTL responses in HLA-A2.1/Kb transgenic mice, as well as in peripheral blood lymphocytes from breast cancer patients. Furthermore, amino-acid substitutions in the P40-48 sequence improved its immunogenicity against hPEBP4, a self-antigen, thus circumventing tolerance. We designed peptide analogs by preferred auxiliary HLA-A*0201 anchor residue replacement, which induced CTLs that were crossreactive to the native peptide. Several analogs were able to stably bind to HLA-A*0201 and elicit specific CTL responses better than the native sequence. Importantly, adoptive transfer of CTLs induced by vaccination with two analogs more effectively inhibited tumor growth than the native peptide. These data indicate that peptide analogs with high immunogenicity represent promising candidates for peptide-mediated therapeutic cancer vaccines.

KEYWORDS:

breast cancer; cytotoxic T lymphocytes; dendritic cells; immunotherapy; peptide epitope

PMID:
29375131
PMCID:
PMC6141579
DOI:
10.1038/cmi.2017.155

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