Targeting CDK7 suppresses super enhancer-linked inflammatory genes and alleviates CAR T cell-induced cytokine release syndrome.
Targeting CDK7 suppresses super enhancer-linked inflammatory genes and alleviates CAR T cell-induced cytokine release syndrome.
复制标题
靶向 CDK7 抑制超级增强子相关炎症基因并缓解 CAR T 细胞诱导的细胞因子释放综合征
DOI：
10.1186/s12943-020-01301-7
复制
发表时间：
2021-01-04
期刊：
影响因子：
37.3
通讯作者：
Su F
中科院分区：
文献类型：
--
作者：
Wei Y;Li C;Bian H;Qian W;Jin K;Xu T;Guo X;Lu X;Su F
细胞因子释放综合征（CRS）是一种以炎症基因过度表达为特征的全身性炎症反应。控制CRS对于提高嵌合抗原受体（CAR）工程T细胞的治疗效果至关重要。然而，鉴于细胞因子相互作用的复杂性，目前的治疗选择是有限的，因此寻求具有广谱抑制的温和策略来克服这一挑战是很重要的。方法利用细胞周期蛋白依赖性激酶7 （cyclin-dependent kinase 7, CDK7）的共价抑制剂THZ1，在活化的巨噬细胞中证实了炎症基因的转录抑制。通过RNA测序和ChIP测序确定炎症反应的关键靶基因。还建立了病原体和CAR - T细胞诱导的CRS模型，以评估靶向CDK7的有效性和安全性。结果scdk7阻断可减轻细胞因子释放，减轻高炎症状态，使小鼠免于致死性CRS。靶向CDK7优先抑制一组炎症基因，其中STAT1和IL1是与超级增强子相关的关键靶点。此外，我们证实了THZ1在缓解CAR - T细胞输注诱导的CRS方面的有效作用，而不会造成组织损伤或损害抗肿瘤作用。结论sour的工作提示炎症基因依赖cdk7的转录依赖性。靶向CDK7是一种很有前景的通过抑制多种细胞因子治疗CRS的策略。
BackgroundCytokine release syndrome (CRS) is a systemic inflammatory response characterized by the overexpression of inflammatory genes. Controlling CRS is essential for improving the therapeutic effects of chimeric antigen receptor (CAR) engineered T cells. However, current treatment options are limited given the complexity of cytokine interactions so it is important to seek a mild strategy with broad-spectrum inhibition to overcome this challenge.MethodsUsing THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), we demonstrated the transcriptional suppression of inflammatory genes in activated macrophages. RNA sequencing and ChIP sequencing were conducted to identify the key target genes of the inflammatory response. Pathogen- and CAR T cell-induced CRS models were also established to assess the efficacy and safety of targeting CDK7.ResultsCDK7 blockade attenuated cytokine release, mitigated hyperinflammatory states and rescued mice from lethal CRS. Targeting CDK7 preferentially suppressed a set of inflammatory genes, of which STAT1 and IL1 were the key targets associated with super enhancers. Furthermore, we confirmed the potent efficacy of THZ1 in alleviating the CRS induced by CAR T cell infusion without causing tissue injury or impairing antitumor effects.ConclusionsOur work indicates the CDK7-dependent transcription addiction of inflammatory genes. Targeting CDK7 is a promising strategy for treating CRS by inhibiting multiple cytokines.
登录
查看更多内容
影响因子：
28.2
作者：
Gust J;Hay KA;Hanafi LA;Li D;Myerson D;Gonzalez-Cuyar LF;Yeung C;Liles WC;Wurfel M;Lopez JA;Chen J;Chung D;Harju-Baker S;Özpolat T;Fink KR;Riddell SR;Maloney DG;Turtle CJ
通讯作者：
Turtle CJ
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.8
作者：
Kwiatkowski, Nicholas;Zhang, Tinghu;Rahl, Peter B.;Abraham, Brian J.;Reddy, Jessica;Ficarro, Scott B.;Dastur, Anahita;Amzallag, Arnaud;Ramaswamy, Sridhar;Tesar, Bethany;Jenkins, Catherine E.;Hannett, Nancy M.;McMillin, Douglas;Sanda, Takaomi;Sim, Taebo;Kim, Nam Doo;Look, Thomas;Mitsiades, Constantine S.;Weng, Andrew P.;Brown, Jennifer R.;Benes, Cyril H.;Marto, Jarrod A.;Young, Richard A.;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
82.9
作者：
Giavridis T;van der Stegen SJC;Eyquem J;Hamieh M;Piersigilli A;Sadelain M
通讯作者：
Sadelain M
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA