Sustained antigen-specific antitumor recall response mediated by gene-modified CD4+ T helper-1 and CD8+ T cells
Sustained antigen-specific antitumor recall response mediated by gene-modified CD4+ T helper-1 and CD8+ T cells
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DOI：
10.1158/0008-5472.can-07-1141
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发表时间：
2007-12-01
期刊：
影响因子：
11.2
通讯作者：
Darcy, Phillip K.
中科院分区：
文献类型：
--
作者：
Moeller, Maria;Kershaw, Michael H.;Darcy, Phillip K.
鉴于辅助性T细胞1（Th 1）和辅助性T细胞2（Th 2）CD 4（+）T细胞的特定亚群已被证明在肿瘤排斥模型中发挥关键作用，我们希望评估Th 1或Th 2 CD 4（+）细胞亚型对重定向T细胞免疫治疗的贡献。在这项研究中，我们开发了一种新的方法，包括逆转录病毒转导和体外T细胞极化，以产生基因工程小鼠CD 4（+）Th 1和Th 2细胞或T辅助性中间（Thi）细胞表达抗erbB 2-CD 28-zeta（嵌合受体）。基因修饰的Thi和Th 2极化的CD 4（+）细胞的特征在于分别优先分泌IFN-γ和白细胞介素-4，而Thi细胞在受体连接后分泌两种细胞因子。在采用erbB 2（+）肺转移模型的过继转移研究中，当转导的Th 1、Th 2或Thi CD 4（+）细胞与等量转导的CD 8（+）T细胞联合转移时，观察到小鼠完全存活。肿瘤排斥反应始终与肿瘤部位的转导T细胞和白细胞介素-2分泌相关。然而，用基因修饰的Th 1 CD 4（+）细胞处理的存活小鼠对随后用皮下植入的不同erbB 2（+）肿瘤（4T1.2）进行的攻击具有显著更强的抵抗力。这一结果与血液中Th 1 CD 4（+）和CD 8（+）T细胞的扩增增加以及再激发后这些细胞定位于肿瘤部位的数量增加相关。这些数据支持使用基因修饰的CD 4（+）Th 1和CD 8（+）T细胞介导持续的抗肿瘤应答。
Given that specific subsets of T helper 1 (Th1) and T helper 2 (Th2) CD4(+) T cells have been shown to play key roles in tumor rejection models, we wanted to assess the contribution of either Th1 or Th2 CD4(+) cell subtypes for redirected T-cell immunotherapy. In this study, we have developed a novel method involving retroviral transduction and in vitro T-cell polarization to generate gene-engineered mouse CD4(+) Th1 and Th2 cells or T helper intermediate (Thi) cells expressing an anti-erbB2-CD28-zeta( chimeric receptor. Gene-modified Thi and Th2 polarized CD4(+) cells were characterized by the preferential secretion of IFN-gamma and interleukin-4, respectively, whereas Thi cells secreted both cytokines following receptor ligation. In adoptive transfer studies using an erbB2(+) lung metastasis model, complete survival of mice was observed when transduced Th1, Th2, or Thi CD4(+) cells were transferred in combination with an equivalent number of transduced CD8(+) T cells. Tumor rejection was consistently associated with transduced T cells at the tumor site and interleukin-2 secretion. However, the surviving mice treated with genemodified Th1 CD4(+) cells were significantly more resistant to a subsequent challenge with a different erbB2(+) tumor (4T1.2) implanted s.c. This result correlated with both increased expansion of Th1 CD4(+) and CD8(+) T cells in the blood and a greater number of these cells localizing to the tumor site following rechallenge. These data support the use of genemodified CD4(+) Th1 and CD8(+) T cells for mediating a sustained antitumor response.