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Identification of new potential antigen recognized by γδT cells in hepatocellular carcinoma

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Abstract

In recent years, the application of chimeric antigen receptor T-cell (CAR-T) therapy based on gamma delta T (γδT) cells in hepatocellular carcinoma (HCC) immunotherapy has attracted more and more attention. However, specific antigens recognized by γδT cells are rarely identified, which has become the main restriction on such therapeutic application of γδT cells. In this report, we identified a new peptide and protein antigen recognized by γδT cells in HCC using our previous established strategy. First, we investigated the diversity of the γ9/δ2 T-cell immunorepertoire by sequence analyses of the expressed complementarity-determining region 3 (CDR3) in HCC patients. Then, we constructed γ9/δ2 T-cell receptor (TCR)-transfected cell lines expressing significant HCC CDR3 sequence and identified a series of peptides capable of binding to γδT cells specifically. Next, we identified, further tested and verified the biological functions of these peptides and their matched protein by bioinformatics analysis. We identified that the new protein hepatocyte growth factor-like protein, also called as macrophage-stimulating protein (MSP), and peptide HP1, not only bound to HCC-predominant γδTCR but also effectively activated γδT cells isolated from HCC patients. Moreover, they could stimulate γδT cells in peripheral blood from HCC patients to produce cytokines, which contributed to inhibiting HCC and played an important role in mediating cytotoxicity to HCC cell lines. In conclusion, we identified MSP and HP1, which showed potential as candidates for antigens recognized by γδT cells in HCC.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81772649,31370890). Innovative Research Program for Graduated of Hubei University of Medicine (YC2019012, YC2020008).

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Author notes

  1. Xueyan Xi, Yang Guo and Min Zhu contributed equally to this report.

Authors and Affiliations

  1. Institute of Basic Medical Sciences, Hubei University of Medicine, No.30 Renmin Nanlu, Shiyan, 442000, Hubei, China

    Xueyan Xi, Yang Guo, Min Zhu, Fen Qiu & Boyu Du

  2. Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, China

    Xueyan Xi

  3. Department of Rheumatology, Renmin Hospital, Hubei University of Medicine, Shiyan, China

    Xueyan Xi, Feifei Lei, Gang Li & Boyu Du

  4. Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China

    Boyu Du

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  1. Xueyan Xi
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  2. Yang Guo
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  3. Min Zhu
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  4. Fen Qiu
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  5. Feifei Lei
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  6. Gang Li
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  7. Boyu Du
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Contributions

Conceived and designed the experiments: XX, BD. Performed the experiments: MZ, YG, FQ. Analyzed the data: XX BD. Contributed reagents/materials/analysis tools: GL FL. Wrote the paper: XX BD.

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Correspondence to Xueyan Xi or Boyu Du.

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The authors declare no conflicts of interest.

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This work received approval from the Clinical Ethics Committee of Hubei University of Medicine (2019-TH-024).

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Xi, X., Guo, Y., Zhu, M. et al. Identification of new potential antigen recognized by γδT cells in hepatocellular carcinoma. Cancer Immunol Immunother 70, 1917–1927 (2021). https://doi.org/10.1007/s00262-020-02826-y

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  • DOI: https://doi.org/10.1007/s00262-020-02826-y

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