4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors.
4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors.
复制标题
DOI：
10.1038/nm.3838
复制
发表时间：
2015-06
期刊：
影响因子：
82.9
通讯作者：
Mackall, Crystal L.
中科院分区：
文献类型：
--
作者：
Long, Adrienne H.;Haso, Waleed M.;Shern, Jack F.;Wanhainen, Kelsey M.;Murgai, Meera;Ingaramo, Maria;Smith, Jillian P.;Walker, Alec J.;Kohler, M. Eric;Venkateshwara, Vikas R.;Kaplan, Rosandra N.;Patterson, George H.;Fry, Terry J.;Orentas, Rimas J.;Mackall, Crystal L.
靶向CD 19的嵌合抗原受体（汽车）在恶性血液病中介导了显着的抗肿瘤反应，但使用靶向其他抗原的汽车很少发生肿瘤消退。目前尚不清楚CD 19汽车的显著作用是否与血液恶性肿瘤对CAR疗法的更大易感性有关，或者与CD 19 CAR本身的上级功能有关。我们发现，由CAR scFv的抗原非依赖性聚集触发的紧张性CAR CD 3 γ磷酸化可以诱导CAR T细胞的早期耗竭，这限制了抗肿瘤功效。这种激活在所研究的所有汽车中以不同程度存在，除了高效的CD 19 CAR。我们进一步确定，CD 28共刺激增强，而4-1BB共刺激改善，由持续的CAR信号转导诱导的耗竭。我们的研究结果为CD 19汽车的显著抗肿瘤作用以及临床试验中CD19.BBz CAR T细胞比CD19.28z CAR T细胞更持久的观察结果提供了生物学解释。
Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic anti-tumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens. It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself. We discovered that tonic CAR CD3ζ phosphorylation, triggered by antigen-independent clustering of CAR scFvs, can induce early exhaustion of CAR T cells that limits anti-tumor efficacy. Such activation is present to varying degrees in all CARs studied, with the exception of the highly effective CD19 CAR. We further identify that CD28 costimulation augments, while 4-1BB costimulation ameliorates, exhaustion induced by persistent CAR signaling. Our results provide biological explanations for the dramatic anti-tumor effects of CD19 CARs and for the observations that CD19.BBz CAR T cells are more persistent than CD19.28z CAR T cells in clinical trials.
登录
查看更多内容
DOI：
10.1084/jem.20052230
发表时间：
2006-09-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Friend LD;Shah DD;Deppong C;Lin J;Bricker TL;Juehne TI;Rose CM;Green JM
通讯作者：
Green JM
影响因子：
11.5
作者：
Kershaw, Michael H.;Westwood, Jennifer A.;Hwu, Patrick
通讯作者：
Hwu, Patrick
影响因子：
10.1
作者：
Hudecek M;Sommermeyer D;Kosasih PL;Silva-Benedict A;Liu L;Rader C;Jensen MC;Riddell SR
通讯作者：
Riddell SR
DOI：
10.1097/cji.0b013e3181ac6138
发表时间：
2009-09
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Kochenderfer JN;Feldman SA;Zhao Y;Xu H;Black MA;Morgan RA;Wilson WH;Rosenberg SA
通讯作者：
Rosenberg SA
DOI：
10.1093/protein/10.4.435
发表时间：
1997-04-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
Nieba, L;Honegger, A;Pluckthun, A
通讯作者：
Pluckthun, A