设为首页收藏本站
开启辅助访问
切换到窄版

 找回密码
 注册

QQ登录

只需一步,快速开始

搜索
查看: 402|回复: 0

4-1BB共刺激域通过诱导CAR 的进补信号来改善T细胞的耗竭

[复制链接]
发表于 2015-8-20 22:08:11 | 显示全部楼层 |阅读模式
4-1BB costimulationameliorates T cell exhaustion induced by tonic signaling of chimeric antigenreceptor
4-1BB共刺激域通过诱导CAR的进补信号来改善T细胞的耗竭
Chimeric antigen receptors (CARs) targeting CD19 havemediated dramatic antitumor responses in hematologic malignancies, but tumorregression has rarely occurred using CARs targeting other antigens. It remainsunknown whether the impressive effects of CD19 CARs relate to greatersusceptibility of hematologic malignancies to CAR therapies, or superiorfunctionality of the CD19 CAR itself. We show that tonic CAR CD3-zphosphorylation, triggered by antigen-independent clustering of CAR single chainvariable fragments, can induce early exhaustion of CAR T cells that limitsantitumor efficacy. Such activation is present to varying degrees in all CARsstudied, except the highly effective CD19 CAR. We further determine that CD28costimulation augments, whereas 4-1BB costimulation reduces, exhaustion inducedby persistent CAR signaling. Our results provide biological explanations forthe antitumor effects of CD19 CARs and for the observations that CD19 CAR Tcells incorporating the 4-1BB costimulatory domain are more persistent thanthose incorporating CD28 in clinical trials.


爱康得生物编译:
靶向CD19嵌合抗原受体(CAR)已证明可在在血液系统恶性肿瘤介导了抗肿瘤反应,但使用其他靶向抗原的CAR-T很少促进肿瘤的消退。我们仍然不知道CAR-T在恶性血液肿瘤取得这么好的效果到底是因为肿瘤本身对CD19CAR-T的敏感性,还是因为CD19CAR-T自身的原因。我们发现,由非抗体引发的CAR单链可变区域的聚集会导致CARCD3-Z磷酸化,并引发CAR-T细胞的过早耗尽,继而限制CAR-T的抗肿瘤效果。这种激活会出现在除CD19CAR以外的多种CAR分子中。我们进一步发现CD28共刺激信号模块的随着4-1BB共刺激减少,持续性的引起CAR信号的耗竭。。我们的研究结果为CD19CAR的抗肿瘤作用和看法提供了生物学解释,即结合了4-1BB共刺激域CD19CAR T细胞比那些在临床试验中结合CD28得更持久。

4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of .pdf

3.59 MB, 下载次数: 36

您需要登录后才可以回帖 登录 | 注册

本版积分规则

QQ|申请友链|小黑屋|手机版|Archiver|生物信息学论坛 ( 蜀ICP备09031721号  

GMT+8, 2017-1-16 20:47 , Processed in 0.156177 second(s), 26 queries .

Powered by Discuz! X3

© 2001-2013 Comsenz Inc.

快速回复 返回顶部 返回列表