Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity

被引：258

作者：

Davenport, A. J. ^{[1
,2
]}

Cross, R. S. ^{[1
,3
,4
]}

Watson, K. A. ^{[3
,4
]}

Liao, Y. ^{[4
,5
]}

Shi, W. ^{[5
,6
]}

Prince, H. M. ^{[1
,2
]}

Beavis, P. A. ^{[1
,2
]}

Trapani, J. A. ^{[1
,2
]}

Kershaw, M. H. ^{[1
,2
]}

Ritchie, D. S. ^{[7
,8
]}

Darcy, P. K. ^{[1
,2
]}

Neeson, P. J. ^{[1
,2
]}

Jenkins, M. R. ^{[1
,2
,3
,4
,9
]}

机构：

[1] Peter MacCallum Canc Ctr, Canc Immunol Res, Melbourne, Vic 3000, Australia

[2] Univ Melbourne, Sir PeterMacCallum Dept Oncol, Parkville, Vic 3000, Australia

[3] Walter & Eliza Hall Inst Med Res, Immunol Div, Parkville, Vic 3052, Australia

[4] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia

[5] Walter & Eliza Hall Inst Med Res, Bioinformat Div, Parkville, Vic 3052, Australia

[6] Univ Melbourne, Dept Comp & Informat Syst, Parkville, Vic 3010, Australia

[7] Melbourne Hlth, Translat Res Lab, Australian Canc Res Fdn, Parkville, Vic 3050, Australia

[8] Univ Melbourne, Dept Med, Parkville, Vic 3010, Australia

[9] La Trobe Univ, Inst Mol Sci, Bundoora, Vic 3086, Australia

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2018年 / 115卷 / 09期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

chimeric antigen receptor; cell death; cytotoxicity; cytotoxic T lymphocyte; immune synapse; MICROTUBULE-ORGANIZING CENTER; IMMUNOLOGICAL SYNAPSE; GRANULE SECRETION; PLASMA-MEMBRANE; POLARIZATION; LCK; LYMPHOCYTES; ACTIVATION; PERFORIN; PROTEIN;

D O I：

10.1073/pnas.1716266115

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：E2068 / E2076

页数：9

共 47 条

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Distinct role of lymphocyte fuinction-associated antigen-1 in mediating effective cytolytic activity by cytotoxic T lymphocytes [J].