Identification of new potential antigen recognized by γδT cells in hepatocellular carcinoma
Identification of new potential antigen recognized by γδT cells in hepatocellular carcinoma
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肝细胞癌中γδT细胞识别的新潜在抗原的鉴定
DOI：
10.1007/s00262-020-02826-y
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发表时间：
2021-01-05
影响因子：
5.8
通讯作者：
Du, Boyu
中科院分区：
文献类型：
--
作者：
Xi, Xueyan;Guo, Yang;Du, Boyu
近年来，基于γ δ T（gamma delta T）细胞的嵌合抗原受体T细胞（CAR-T）疗法在肝细胞癌（HCC）免疫治疗中的应用越来越受到关注。然而，γ δ T细胞识别的特异性抗原很少被鉴定，这已经成为γ δ T细胞的这种治疗应用的主要限制。在这份报告中，我们确定了一个新的肽和蛋白质抗原识别的γ δ T细胞在肝癌中使用我们以前建立的战略。首先，我们通过对肝癌患者表达的互补决定区3（CDR 3）进行序列分析，研究了γ 9/δ 2 T细胞免疫组化的多样性。然后，我们构建了γ 9/δ 2 T细胞受体（TCR）转染的细胞系，表达显著的HCC CDR 3序列，并鉴定了一系列能够特异性结合γ δ T细胞的肽。接下来，我们通过生物信息学分析，对这些肽及其匹配蛋白的生物学功能进行了鉴定、进一步测试和验证。我们发现，新的蛋白质肝细胞生长因子样蛋白，也称为巨噬细胞刺激蛋白（MSP），和肽HP 1，不仅结合到肝癌占主导地位的γ δ TCR，但也有效地激活γ δ T细胞分离自肝癌患者。此外，它们可以刺激肝癌患者外周血中的γ δ T细胞产生细胞因子，这有助于抑制肝癌，并在介导对肝癌细胞系的细胞毒性中发挥重要作用。总之，我们鉴定了MSP和HP 1，其显示出作为HCC中γ δ T细胞识别的抗原的候选者的潜力。
In recent years, the application of chimeric antigen receptor T-cell (CAR-T) therapy based on gamma delta T (gamma delta T) cells in hepatocellular carcinoma (HCC) immunotherapy has attracted more and more attention. However, specific antigens recognized by gamma delta T cells are rarely identified, which has become the main restriction on such therapeutic application of gamma delta T cells. In this report, we identified a new peptide and protein antigen recognized by gamma delta T cells in HCC using our previous established strategy. First, we investigated the diversity of the gamma 9/delta 2 T-cell immunorepertoire by sequence analyses of the expressed complementarity-determining region 3 (CDR3) in HCC patients. Then, we constructed gamma 9/delta 2 T-cell receptor (TCR)-transfected cell lines expressing significant HCC CDR3 sequence and identified a series of peptides capable of binding to gamma delta T 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 gamma delta TCR but also effectively activated gamma delta T cells isolated from HCC patients. Moreover, they could stimulate gamma delta T 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 gamma delta T cells in HCC.