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

Cellular & Molecular Immunology volume 15, pages 768–781 (2018)Cite this article

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.

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Acknowledgements

We thank Drs Xiaojian Wang, Zhenhong Guo, Hongzhe Li, Liyun Shi and Jianming Qiu for helpful discussions. This work was supported by grants from the National Key Basic Research Program of China (2013CB530502) (to NL), the National Natural Science Foundation of China (81672798 to NL, 81672736 to YL, 31670875 to SL, 81671644 to YW, 81788104 to XC) and the Shanghai Committee of Science and Technology (09QH1402800, 09SG35) (to NL).

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Authors and Affiliations

  1. National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, 200433, China

    Weihong Sun, Huabiao Chen, Shuxun Liu, Yanfeng Wu, Xuetao Cao & Nan Li

  2. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China

    Weihong Sun, Jian Wu & Xuetao Cao

  3. Biotherapy Center, The Affiliated Central Hospital of Qingdao University, Qingdao, 266042, China

    Weihong Sun, Jian Wu & Xuetao Cao

  4. Department of Surgery, Changhai Hospital, Shanghai, 200433, China

    Junyi Shi

  5. Department of Surgery, Changzheng Hospital, Shanghai, 200003, China

    Junchu Zhang

  6. Shanghai Center for Bioinformation Technology, Shanghai, 201203, China

    Yuanyuan Li

  7. Institute of Immunology, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China

    Zhigang Tian

  8. National Key Laboratory of Medical Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, Beijing, 100005, China

    Xuetao Cao

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  1. Weihong Sun
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Correspondence to Nan Li.

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Sun, W., Shi, J., Wu, J. et al. A modified HLA-A*0201-restricted CTL epitope from human oncoprotein (hPEBP4) induces more efficient antitumor responses. Cell Mol Immunol 15, 768–781 (2018). https://doi.org/10.1038/cmi.2017.155

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