Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity.
Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity.
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DOI：
10.1073/pnas.1716266115
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发表时间：
2018-02-27
影响因子：
11.1
通讯作者：
Jenkins MR
中科院分区：
文献类型：
--
作者：
Davenport AJ;Cross RS;Watson KA;Liao Y;Shi W;Prince HM;Beavis PA;Trapani JA;Kershaw MH;Ritchie DS;Darcy PK;Neeson PJ;Jenkins MR
Davenport等人发现嵌合抗原受体（CAR）免疫突触结构不同于T细胞受体（TCR）突触。CAR免疫突触形成Lck的无序模式，并且与TCR相比更快速地募集溶解颗粒。不同的免疫突触与CAR-T细胞更快地杀死肿瘤靶细胞和从垂死的肿瘤细胞中脱离相关。这些发现提供了一种机制，CAR-T细胞可以有效地减少患者的大肿瘤负担。这项研究将形成一个基础，在此基础上比较未来的受体设计，以调节细胞毒性CAR-T细胞的信号传导和编程，从而改善实体癌的治疗。嵌合抗原受体T（CAR-T）细胞是有效的连环杀手，与CAR-T细胞通过其T细胞受体（TCR）结合靶细胞相比，其从垂死肿瘤细胞的解离速率更快。在这里，我们使用双特异性CAR-T细胞探索了CAR介导的信号传导的功能后果，其中相同的细胞通过TCR（tcrCTL）或CAR（carCTL）触发。carCTL免疫突触缺乏明显的LFA-1粘附环，并且不太依赖LFA与靶细胞形成稳定的缀合物。发现与突触相关的carCTL受体被破坏并形成Lck微簇的卷曲多灶模式。近端和远端受体信号传导途径在carCTL中比在tcrCTL中诱导得更快，随后下降得更快。carCTL细胞中这种快速信号传导的功能结果包括更快的溶解颗粒募集到免疫突触，与CTL从靶细胞的更快脱离相关。这项研究为CAR-T细胞如何快速减少大肿瘤负荷提供了一种机制，并可能有助于进一步完善CAR设计，以提高T细胞的信号传导和编程质量。
Davenport et al. discovered that the chimeric antigen receptor (CAR) immune synapse structure is different from the T cell receptor (TCR) synapse. The CAR immune synapse formed a disorganized pattern of Lck and more rapidly recruited lytic granules compared with the TCR. The differing immune synapse correlated with faster killing of tumor target cells and detachment from dying tumor cells by CAR-T cells. These findings provide a mechanism whereby CAR-T cells can effectively reduce large tumor burden in patients. This study will form a basis upon which to compare future receptor design to modulate signaling and programming of cytotoxic CAR-T cells to improve treatment of solid cancers. Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters. Both proximal and distal receptor signaling pathways were induced more rapidly and subsequently decreased more rapidly in carCTL than in tcrCTL. The functional consequence of this rapid signaling in carCTL cells included faster lytic granule recruitment to the immune synapse, correlating with faster detachment of the CTL from the target cell. This study provides a mechanism for how CAR-T cells can debulk large tumor burden quickly and may contribute to further refinement of CAR design for enhancing the quality of signaling and programming of the T cell.
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影响因子：
3.7
作者：
Karlsson H;Svensson E;Gigg C;Jarvius M;Olsson-Strömberg U;Savoldo B;Dotti G;Loskog A
通讯作者：
Loskog A
影响因子：
64.8
作者：
Monks, CRF;Freiberg, BA;Kupfer, A
通讯作者：
Kupfer, A
DOI：
10.1073/pnas.1218640110
发表时间：
2013-04-09
影响因子：
11.1
作者：
Bertrand, Florie;Mueller, Sabina;Valitutti, Salvatore
通讯作者：
Valitutti, Salvatore
影响因子：
20.3
作者：
Burns, William R.;Zheng, Zhili;Morgan, Richard A.
通讯作者：
Morgan, Richard A.
影响因子：
4.4
作者：
Graf, Beth;Bushnell, Timothy;Miller, Jim
通讯作者：
Miller, Jim