Chimeric Antigen Receptor T Cell Bearing Herpes Virus Entry Mediator Co-stimulatory Signal Domain Exhibits High Functional Potency
Chimeric Antigen Receptor T Cell Bearing Herpes Virus Entry Mediator Co-stimulatory Signal Domain Exhibits High Functional Potency
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DOI：
10.1016/j.omto.2019.03.002
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发表时间：
2019-03
期刊：
影响因子：
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通讯作者：
Jun-ichi Nunoya;M. Masuda;Chaobaihui Ye;L. Su
中科院分区：
文献类型：
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作者：
Jun-ichi Nunoya;M. Masuda;Chaobaihui Ye;L. Su
嵌合抗原受体(CAR)是由抗原结合区和信号转导区组成的杂合分子。表达CAR(CAR-T细胞)的人工T细胞有望成为治疗癌症等各种疾病的有用工具。CAR中加入共刺激信号域(CSSD)是调节CAR-T细胞活性的关键。然而，CSSD的类型、效应器功能和CAR-T细胞特性之间的相互作用在很大程度上是未知的。为了阐明这种相互作用，我们分析了不同CSSD的CAR-T细胞的效应器功能、向记忆T细胞亚群的分化、衰竭和能量代谢。与目前用于CAR-T细胞发育的携带CD28或4-1BB来源CSSD的CAR-T细胞相比，我们发现带有疱疹病毒进入介体(HSEM)来源CSSD的CAR-T细胞具有增强的效应功能，并有效和平衡地分化为中枢和效应记忆亚群，与能量代谢的提高和耗竭水平的降低有关。因此，我们开发了携带来源于HVEM的CSSD的具有高功能潜能的CAR-T细胞。HSEM来源的CSSD可能有助于开发有效的CAR-T细胞。
Chimeric antigen receptor (CAR) is a hybrid molecule consisting of an antigen-binding domain and a signal transduction domain. The artificial T cells expressing CAR (CAR-T cells) are expected to be a useful tool for treatment of various diseases, such as cancer. The addition of a co-stimulatory signal domain (CSSD) to CAR is shown to be critical for modulating CAR-T cell activities. However, the interplay among types of CSSDs, effector functions, and characteristics of CAR-T cells is largely unknown. To elucidate the interplay, we analyzed effector functions, differentiation to memory T cell subsets, exhaustion, and energy metabolism of the CAR-T cells with different CSSDs. Comparing to the CAR-T cells bearing a CD28- or 4-1BB-derived CSSD, which are currently used for CAR-T cell development, we found that the CAR-T cells with a herpes virus entry mediator (HVEM)-derived CSSD exhibited enhanced effector functions and efficient and balanced differentiation to both central and effector memory subsets, associated with an elevated energy metabolism and a reduced level of exhaustion. Thus, we developed the CAR-T cells bearing the CSSD derived from HVEM with high functional potency. The HVEM-derived CSSD may be useful for developing effective CAR-T cells.