TCRγ4δ1-Engineered αβT Cells Exhibit Effective Antitumor Activity
TCRγ4δ1-Engineered αβT Cells Exhibit Effective Antitumor Activity
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TCR gamma 4 delta 1-工程化 alpha beta T 细胞表现出有效的抗肿瘤活性
DOI：
10.2119/molmed.2016.00023
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发表时间：
2016-01-01
影响因子：
5.7
通讯作者：
He, Wei
中科院分区：
文献类型：
--
作者：
He, Kangxia;You, Hongqin;He, Wei
具有肿瘤特异性 T 细胞受体 (TCR) 的 T 细胞工程在癌症过继性 T 细胞转移 (ATC) 治疗中发挥着重要作用。在这里，我们提出了一种新策略，通过 TCR gamma 4 delta 1 基因转导将外周血来源的 alpha beta T 细胞重新定向以对抗肿瘤。 TCR δ 1 细胞在先天免疫中的广谱抗肿瘤活性依赖于 CDR3 δ 1。通过慢病毒转导制备 TCR γ 4 δ 1 工程化的 αβ T 细胞，并通过分析体外和体内对肿瘤的细胞毒性、增殖和细胞因子产生的能力以及在自身免疫中的潜在作用来表征。结果显示，TCR gamma 4 delta 1 基因被转导至大约 36% 的多克隆 alpha beta T 细胞。 TCR gamma 4 delta 1 工程化的 alpha beta T 细胞通过穿孔素-颗粒酶途径对各种肿瘤细胞表现出有效的体外 TCR gamma delta 依赖性细胞毒性。它们还表现出强大的增殖能力和强大的细胞因子产生能力。 TCR gamma 4 delta 1 工程化的 alpha beta T 细胞在体外既不表达混合 TCR 二聚体，也不结合/杀死正常细胞。更重要的是，将 TCR gamma 4 delta 1 工程化的 alpha beta T 细胞过继转移到携带人 HepG2 细胞系的裸鼠体内，可显着抑制肿瘤生长。我们的结果证明了 TCR gamma 4 delta 1 在癌症基因治疗和 ATC 中的新作用。
T cell engineering with T cell receptors (TCRs) specific for tumors plays an important role in adoptive T cell transfer (ATC) therapy for cancer. Here, we present a novel strategy to redirect peripheral blood-derived alpha beta T cells against tumors via TCR gamma 4 delta 1 gene transduction. The broad-spectrum antitumor activity of TCR delta 1 cells in innate immunity is dependent on CDR3 delta 1. TCR gamma 4 delta 1-engineered alpha beta T cells were prepared by lentiviral transduction and characterized by analyzing in vitro and in vivo cytotoxicity to tumors, ability of proliferation and cytokine production, and potential role in autoimmunity. Results show that TCR gamma 4 delta 1 genes were transduced to approximately 36% of polyclonal alpha beta T cells. TCR gamma 4 delta 1-engineered alpha beta T cells exhibited effective in vitro TCR gamma delta-dependent cytotoxicity against various tumor cells via the perforin-granzyme pathway. They also showed a strong proliferative capacity and robust cytokine production. TCR gamma 4 delta 1-engineered alpha beta T cells neither expressed mixed TCR dimers nor bound/killed normal cells in vitro. More important, adoptive transfer of TCR gamma 4 delta 1-engineered alpha beta T cells into nude mice bearing a human HepG2 cell line significantly suppressed tumor growth. Our results demonstrate a novel role for TCR gamma 4 delta 1 in gene therapy and ATC for cancer.