T lymphocytes engineered to express a CD16-chimeric antigen receptor redirect T-cell immune responses against immunoglobulin G-opsonized target cells
T lymphocytes engineered to express a CD16-chimeric antigen receptor redirect T-cell immune responses against immunoglobulin G-opsonized target cells
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DOI：
10.1016/j.jcyt.2015.10.014
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发表时间：
2016-02-01
期刊：
影响因子：
4.5
通讯作者：
Alimandi, Maurizio
中科院分区：
文献类型：
--
作者：
D'Aloia, Maria Michela;Caratelli, Sara;Alimandi, Maurizio
背景目标。设计用于过继免疫治疗的嵌合抗原受体（汽车）需要实现两种功能：抗原识别和触发重编程效应细胞的裂解机制。细胞毒性T细胞已经用Fc γ RIII（CD 16）嵌合分子工程化，以通过单克隆抗体（mAb）重定向针对恶性细胞。这些细胞已被证明介导颗粒依赖性细胞毒性，但尚不清楚它们是否也可以通过颗粒非依赖性细胞毒性机制杀死恶性细胞。方法.我们设计了一种CD 16 A-CAR，其配备有细胞外CD 16 A、铰链间隔区和CD 8的跨膜区，以及与CD 28共刺激信号转导模块串联的T细胞受体/CD 3复合物的ζ链。在MD 45细胞系中表达CD 16 A-CAR并进行功能测试，MD 45细胞系是一种具有缺陷性颗粒胞吐途径但能够通过Fas配体介导的裂解杀死靶细胞的鼠T细胞杂交瘤。结果我们的结果表明，在体外交联的CD 16 A-CAR的MD 45细胞上的mAb调理肿瘤细胞的Fc片段诱导白细胞介素-2释放和颗粒非依赖性细胞毒性。结论.我们得出结论，旨在实现临床使用的mAb的治疗功能的策略，其中T依赖性免疫应答由表达Fc γ R-CAR的工程化T细胞驱动，可以增强临床使用的mAb的抗肿瘤功效。
Background aims. Chimeric antigen receptors (CARs) designed for adoptive immunotherapy need to achieve two functions: antigen recognition and triggering of the lytic machinery of reprogrammed effector cells. Cytotoxic T cells have been engineered with Fc gamma RIII (CD16) chimeric molecules to be redirected against malignant cells by monoclonal antibodies (mAbs). These cells have been proven to mediate granule-dependent cellular cytotoxicity, but it is not clear whether they can also kill malignant cells by a granule-independent mechanism of cell cytotoxicity. Methods. We engineered a CD16A-CAR equipped with the extracellular CD16A, the hinge spacer and the transmembrane region of CD8, and the zeta-chain of the T-cell receptor/CD3 complex in tandem with the CD28 co-stimulatory signal transducer module. The CD16A-CAR was expressed and functionally tested in the MD45 cell line, a murine T-cell hybridoma with a defective granular exocytosis pathway but capable of killing target cells by a Fas ligand mediated lysis. Results. Our results indicate that in vitro cross-linking of CD16A-CAR on MD45 cells by the Fc fragment of mAb opsonized tumor cells induced interleukin-2 release and granule-independent cellular cytotoxicity. Conclusions. We conclude that strategies aimed to implement the therapeutic functions of mAbs used in the clinic with T-dependent immune responses driven by engineered T cells expressing Fc gamma R-CAR can boost the antitumor efficacy of mAbs used in the clinic.