Targeting CDK7 suppresses super enhancer-linked inflammatory genes and alleviates CAR T cell-induced cytokine release syndrome

• Published in: Molecular cancer 2021-01, Vol.20 (1), p.5-18, Article 5
• Main Authors: Wei, Ye, Li, Chong, Bian, Huifang, Qian, Wei, Jin, Kairui, Xu, Tingting, Guo, Xiaomao, Lu, Xueguan, Su, Fengtao
• Format: Article
• Language: English
• Subjects: Addictions; Animals; Antigens; Antineoplastic Agents - pharmacology; Antitumor activity; Cell culture; Chimeric antigen receptor engineered T cells; Chimeric antigen receptors; Cyclin-dependent kinase 7; Cyclin-Dependent Kinase-Activating Kinase; Cyclin-dependent kinases; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclin-Dependent Kinases - metabolism; Cytokine release syndrome; Cytokine Release Syndrome - etiology; Cytokine storm; Cytokines; Deoxyribonucleic acid; DNA; Enhancer Elements, Genetic - genetics; Enhancers; Enzyme inhibitors; Experiments; Female; Gene Expression Profiling; Genes; Genetic aspects; Genetic engineering; Genetic transcription; Health aspects; Humans; Immunotherapy; Immunotherapy, Adoptive - adverse effects; Inflammation; Inflammation - genetics; Inflammation - pathology; Inflammatory diseases; Inflammatory genes; Interleukin 1; Kinases; Lipopolysaccharides; Lymphocytes; Lymphocytes T; Lymphoma; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Models, Biological; Neurotoxicity; Ontology; Phenylenediamines - pharmacology; Protein Kinase Inhibitors - pharmacology; Pyrimidines - pharmacology; Ribonucleic acid; RNA; RNA polymerase; RNA Polymerase II - metabolism; RNA sequencing; Software; Stat1 protein; Super enhancer; T cells; Transcription; Transcription, Genetic - drug effects; Tumor necrosis factor-TNF
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-020-01301-7

Cytokine 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. Using 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. CDK7 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. Our work indicates the CDK7-dependent transcription addiction of inflammatory genes. Targeting CDK7 is a promising strategy for treating CRS by inhibiting multiple cytokines.