Generation and targeting of human tumor-specific Tc1 and Th1 cells transduced with a lentivirus containing a chimeric immunoglobulin T-cell receptor
Generation and targeting of human tumor-specific Tc1 and Th1 cells transduced with a lentivirus containing a chimeric immunoglobulin T-cell receptor
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DOI：
10.1158/0008-5472.can-03-2780
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发表时间：
2004-02-15
期刊：
影响因子：
11.2
通讯作者：
Nishimura, T
中科院分区：
文献类型：
--
作者：
Gyobu, H;Tsuji, T;Nishimura, T
CD4(+)Th细胞，特别是产生干扰素-γ的Th1细胞，在Tc1细胞的激活和维持中起着关键作用，而Tc1细胞是肿瘤根除所必需的。在这里，我们报告了使用慢病毒转导系统从非特异性激活的T细胞中产生人工肿瘤特异性Th1和Tc1细胞。用慢病毒转导来自健康供者的抗CD3激活的T细胞，慢病毒含有嵌合免疫球蛋白T细胞受体基因，该嵌合免疫球蛋白T细胞受体基因由抗癌胚抗原(CEA)特异性单抗的单链可变片段与CD28和CD3zeta胞浆部分的胞内信号域融合而成。这些人工的肿瘤特异性Tc1和Th1细胞，分别被称为Tc1-和Th1-T小体，可以靶向CEA(+)肿瘤细胞，而不受MHC限制。具体地说，Tc1-T小体对CEA(+)肿瘤细胞株有较高的细胞毒作用，并能产生干扰素-γ，但对CEA(-)肿瘤细胞无反应。尽管Th1-T小体表现出低的细胞毒性，但它们能分泌高水平的干扰素-γ和白介素2来应答CEA(+)肿瘤细胞。在模拟基因转导的非特异性Tc1和Th1细胞中未观察到这种CEA(+)肿瘤特异性激活。此外，Tc1-和Th1-T抗体对移植到RAG2(-/-)小鼠体内的CEA(+)人肺癌细胞具有很强的抗肿瘤活性。此外，与Tc1和Th1-T小体联合治疗可增强体内的抗肿瘤活性。综上所述，我们的发现表明，Tc1和Th1-T小体是目前开发有效过继免疫疗法的一种有前途的替代方法。
CD4(+) Th cells, in particular IFN-gamma-producing Th1 cells, play a critical role in the activation and maintenance of Tc1 cells that are essential for tumor eradication. Here, we report the generation of artificial tumor-specific Th1 and Tc1 cells from nonspecifically activated T cells using a lentiviral transduction system. Anti-CD3-activated T cells from healthy human donors were transduced with a lentivirus containing a chimeric immunoglobulin T-cell receptor gene composed of single-chain variable fragments derived from an anticarcinoembryonic antigen (CEA)-specific monoclonal antibody fused to an intracellular signaling domain derived from the cytoplasmic portions of membrane-bound CD28 and CD3zeta. These artificial tumor-specific Tc1 and Th1 cells, termed Tc1- and Th1-T bodies, respectively, could be targeted to CEA(+) tumor cells independently of MHC restriction. Specifically, Tc1-T bodies demonstrated high cytotoxicity and produced IFN-gamma in response to CEA(+) tumor cell lines but not CEA(-) tumors. Although Th1-T bodies exhibited low cytotoxicity, they secreted high levels of IFN-gamma and interleukin-2 in response to CEA(+) tumor cells. Such CEA(+) tumor-specific activation was not observed in mock gene-transduced nonspecific Tc1 and Th1 cells. Moreover, Tc1- and Th1-T bodies exhibited strong antitumor activities against CEA(+) human lung cancer cells implanted into RAG2(-/-) mice. Furthermore, combined therapy with Tc1- and Th1-T bodies resulted in enhanced antitumor activities in vivo. Taken together, our findings demonstrate that Tc1- and Th1-T bodies represent a promising alternative to current methods for the development of effective adoptive immunotherapies.