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

Ye Wei,Ye Wei,Kairui Jin,Xueguan Lu,Kairui Jin,Tingting Xu,Xueguan Lu,Chong Li,Chong Li,Huifang Bian,Tingting Xu,Fengtao Su,Fengtao Su,Wei Qian,Wei Qian,Huifang Bian,Xiaomao Guo,Xiaomao Guo

doi:10.1186/s12943-020-01301-7

Abstract

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.

Highlights

Cytokine release syndrome (CRS) is a systemic inflammatory response characterized by the overexpression of inflammatory genes
In chimeric antigen receptor (CAR) T models, evidence has shed light on that the severity of CRS is not totally mediated by cytokines derived from CAR T cells, but by factors derived from the recipient macrophages [8, 9]
According to the Gene Ontology (GO) enrichment analysis, we found a high overlap of biological processes between 701 Differentially expressed gene (DEG) stimulated by LPS and 361 DEGs that were sensitive to THZ1 (Fig. 3b, Supplementary Table)

Summary

Introduction

Cytokine release syndrome (CRS) is a systemic inflammatory response characterized by the overexpression of inflammatory genes. In CAR T models, evidence has shed light on that the severity of CRS is not totally mediated by cytokines derived from CAR T cells, but by factors derived from the recipient macrophages [8, 9]. This conclusion is supported by several studies focused on CAR T therapy-induced encephalopathy, a delayed neurotoxicity which had previously been ascribed to the cytokine release of CAR T cells [10]. Seeking a mild anti-inflammatory strategy with broad-spectrum inhibition is necessary to overcome this challenge

Methods

Results

Discussion

Conclusion