Chimeric Antigen Receptors Combining 4-1BB and CD28 Signaling Domains Augment PI3kinase/AKT/Bcl-XL Activation and CD8+ T Cell-mediated Tumor Eradication
Chimeric Antigen Receptors Combining 4-1BB and CD28 Signaling Domains Augment PI3kinase/AKT/Bcl-XL Activation and CD8+ T Cell-mediated Tumor Eradication
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DOI：
10.1038/mt.2009.210
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发表时间：
2010-02-01
影响因子：
12.4
通讯作者：
Sadelain, Michel
中科院分区：
文献类型：
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作者：
Zhong, Xiao-Song;Matsushita, Maiko;Sadelain, Michel
为了增强肿瘤抗原特异性受体所提供的激活强度，我们研究了在一种针对前列腺特异性膜抗原（PSMA）的嵌合抗原受体（CAR）中添加联合的CD28和4 - 1BB共刺激信号结构域的效果。在将包含CD28、4 - 1BB和/或CD3ζ胞质结构域的受体转导至原代人CD8⁺T细胞后，我们发现包含所有三个信号结构域的P28BBz受体在促进细胞因子释放、体内T细胞存活以及向荷瘤重症联合免疫缺陷（SCID）/ beige小鼠静脉注射T细胞后的肿瘤清除方面，优于仅包含这些结构域中的一个或两个的受体。在体外暴露于PSMA时，P28BBZ受体在转导的外周血CD8⁺T细胞中诱导了最强的PI3激酶/Akt激活和Bcl - X - L表达，以及最少的细胞凋亡。这些发现进一步支持了将优化的共刺激特性整合到重组抗原受体中以增强基因靶向T细胞在肿瘤微环境中的存活和功能这一概念。
To enhance the strength of activation afforded by tumor antigen-specific receptors, we investigated the effect of adding combined CD28 and 4-1BB costimulatory signaling domains to a chimeric antigen receptor (CAR) specific for prostate-specific membrane antigen (PSMA). Having transferred receptors encompassing the CD28, 4-1BB, and/or CD3 zeta cytoplasmic domains in primary human CD8+ T cells, we find that the P28BBz receptor, which includes all three signaling domains, is superior to receptors that only include one or two of these domains in promoting cytokine release, in vivo T-cell survival and tumor elimination following intravenous T-cell administration to tumor-bearing severe combined immunodeficient (SCID)/beige mice. Upon in vitro exposure to PSMA, the P28BBZ receptor-induced the strongest PI3 Kinase/Akt activation and Bcl-X-L expression, and the least apoptosis in transduced peripheral blood CD8+ T cells. These findings further support the concept of integrating optimized costimulatory properties into recombinant antigen receptors to augment the survival and function of genetically targeted T cells within the tumor micro-environment.