Human T Cells Engineered To Express a Programmed Death 1/28 Costimulatory Retargeting Molecule Display Enhanced Antitumor Activity
Human T Cells Engineered To Express a Programmed Death 1/28 Costimulatory Retargeting Molecule Display Enhanced Antitumor Activity
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DOI：
10.4049/jimmunol.1203085
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发表时间：
2013-10-15
影响因子：
4.4
通讯作者：
Cohen, Cyrille J.
中科院分区：
文献类型：
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作者：
Ankri, Chen;Shamalov, Katerina;Cohen, Cyrille J.
过继转移表达癌症特异性受体的基因修饰的T细胞可以在绝症患者中介导令人印象深刻的肿瘤消退。然而，T细胞的功能和持续时间可能受到抑制共刺激通路的激活，如程序性死亡1(PD1)/程序性死亡配体1，导致T细胞耗尽，并为肿瘤细胞提供逃避免疫监视的机制。此外，肿瘤部位缺乏正向共刺激会进一步抑制T细胞的反应。因此，由于T细胞基因工程已经成为临床相关的，我们的目标是通过使用嵌合的共刺激分子将T细胞阴性的共刺激信号遗传地转移到阳性的共刺激信号中来增强T细胞的抗肿瘤活性。嵌合的共刺激分子是由PD1胞外区与阳性的共刺激分子的信号域融合而成的，如CD28和4-1BB。在鉴定了最佳的PD1嵌合体后，我们设计并优化了一个三方逆转录病毒载体，使该嵌合分子能够与癌症特异性TCR一起同时表达。转导表达PD1/28嵌合分子的人T细胞与肿瘤细胞共培养时，细胞因子分泌增强，活化标志物上调。与对照细胞相比，这些工程细胞的增殖情况也更好。最后，我们在两种人黑色素瘤移植模型中测试了这些细胞的功能，结果表明，PD1/28工程化的人T细胞表现出了优越的抗肿瘤功能。综上所述，我们提出用共刺激分子重组T细胞可以增强其功能，这对改进T细胞免疫治疗具有重要意义。
Adoptive transfer of T cells genetically modified to express cancer-specific receptors can mediate impressive tumor regression in terminally ill patients. However, T cell function and persistence over time could be hampered by the activation of inhibitory costimulatory pathways, such as programmed death 1 (PD1)/programmed death ligand 1, leading to T cell exhaustion and providing tumor cells with an escape mechanism from immunosurveillance. In addition, the lack of positive costimulation at the tumor site can further dampen T cell response. Thus, as T cell genetic engineering has become clinically relevant, we aimed at enhancing T cell antitumor activity by genetically diverting T cell-negative costimulatory signals into positive ones using chimeric costimulatory retargeting molecules and which are composed of the PD1 extracellular domain fused to the signaling domains of positive costimulatory molecules such as CD28 and 4-1BB. After characterizing the optimal PD1 chimera, we designed and optimized a tripartite retroviral vector that enables the simultaneous expression of this chimeric molecule in conjunction with a cancer-specific TCR. Human T cells, transduced to express a PD1/28 chimeric molecule, exhibited enhanced cytokine secretion and upregulation of activation markers upon coculture with tumor cells. These engineered cells also proliferated better compared with control cells. Finally, we tested the function of these cells in two xenograft models of human melanoma tumors and show that PD1/28-engineered human T cells demonstrated superior antitumor function. Overall, we propose that engineering T cells with a costimulatory retargeting molecule can enhance their function, which bears important implications for the improvement of T cell immunotherapy.