CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy.
CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy.
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DOI：
10.1038/s41467-021-23331-5
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发表时间：
2021-05-28
影响因子：
16.6
通讯作者：
Beavis PA
中科院分区：
文献类型：
--
作者：
Giuffrida L;Sek K;Henderson MA;Lai J;Chen AXY;Meyran D;Todd KL;Petley EV;Mardiana S;Mølck C;Stewart GD;Solomon BJ;Parish IA;Neeson PJ;Harrison SJ;Kats LM;House IG;Darcy PK;Beavis PA
腺苷是一种免疫抑制因子，通过激活腺苷A2A受体（A2AR）抑制包括T细胞在内的多种免疫亚群，从而限制抗肿瘤免疫。使用小鼠和人嵌合抗原受体（CAR） T细胞，我们发现用临床相关的CRISPR/Cas9策略靶向A2AR显著提高了它们的体内功效，从而提高了小鼠的存活率。CRISPR/Cas9介导的A2AR基因缺失诱发的效果优于shRNA介导的A2AR敲低或药物阻断。从机制上讲，人类a2ar编辑的CAR - T细胞对腺苷介导的转录变化具有显著的抗性，导致IFNγ和TNF等细胞因子的产生增加，JAK-STAT信号通路相关基因的表达增加。缺乏A2AR的CAR - T细胞在小鼠中耐受性良好，不会诱发明显的病理，这支持在临床中使用CRISPR/Cas9靶向A2AR来改善CAR - T细胞的功能。腺苷受体A2AR的激活与肿瘤微环境中T细胞功能的抑制有关。为了克服免疫抑制，本文作者表明，CRISPR/Cas9介导的A2AR缺失增强了CAR-T细胞效应功能，而不改变记忆或持久性，从而改善了临床前模型中CAR-T介导的肿瘤控制。
Adenosine is an immunosuppressive factor that limits anti-tumor immunity through the suppression of multiple immune subsets including T cells via activation of the adenosine A2A receptor (A2AR). Using both murine and human chimeric antigen receptor (CAR) T cells, here we show that targeting A2AR with a clinically relevant CRISPR/Cas9 strategy significantly enhances their in vivo efficacy, leading to improved survival of mice. Effects evoked by CRISPR/Cas9 mediated gene deletion of A2AR are superior to shRNA mediated knockdown or pharmacological blockade of A2AR. Mechanistically, human A2AR-edited CAR T cells are significantly resistant to adenosine-mediated transcriptional changes, resulting in enhanced production of cytokines including IFNγ and TNF, and increased expression of JAK-STAT signaling pathway associated genes. A2AR deficient CAR T cells are well tolerated and do not induce overt pathologies in mice, supporting the use of CRISPR/Cas9 to target A2AR for the improvement of CAR T cell function in the clinic. Activation of the adenosine receptor A2AR is associated with suppression of T cell function in the tumor microenvironment. To overcome immunosuppression, here the authors show that CRISPR/Cas9 mediated deletion of A2AR enhances CAR T cell effector functions without altering memory or persistence properties, improving CAR-T mediated tumor control in pre-clinical models.
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影响因子：
15.9
作者：
Jayaprakash, Priyamvada;Ai, Midan;Curran, Michael A.
通讯作者：
Curran, Michael A.
DOI：
10.1038/mtna.2014.64
发表时间：
2014-12-02
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
通讯作者：
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影响因子：
11.2
作者：
Cekic C;Linden J
通讯作者：
Linden J
影响因子：
10.1
作者：
Beavis, Paul A.;Milenkovski, Nicole;Darcy, Phillip K.
通讯作者：
Darcy, Phillip K.
影响因子：
16.6
作者：
LaFleur, Martin W.;Nguyen, Thao H.;Sharpe, Arlene H.
通讯作者：
Sharpe, Arlene H.