Snyder Katiri J, Choe Hannah K, Gao Yandi, Sell Natalie E, Braunreiter Kara M, Zitzer Nina C, Neidemire-Colley Lotus, Kalyan Sonu, Dorrance Adrienne M, Keller Andrea, Mihaylova Maria M, Singh Satishkumar, Sehgal Lalit, Bollag Gideon, Ma Yan, Powell Ben, Devine Steven M, Ranganathan Parvathi
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States.
Department of Biological Chemistry and Pharmacology, Comprehensive Cancer Center, The Ohio State University Columbus, Columbus, OH, United States.
Front Oncol. 2021 Oct 15;11:760789. doi: 10.3389/fonc.2021.760789. eCollection 2021.
Acute graft--host disease (GVHD) is the leading cause of non-relapse mortality following allogeneic hematopoietic cell transplantation. The majority of patients non-responsive to front line treatment with steroids have an estimated overall 2-year survival rate of only 10%. Bromodomain and extra-terminal domain (BET) proteins influence inflammatory gene transcription, and therefore represent a potential target to mitigate inflammation central to acute GVHD pathogenesis. Using potent and selective BET inhibitors Plexxikon-51107 and -2853 (PLX51107 and PLX2853), we show that BET inhibition significantly improves survival and reduces disease progression in murine models of acute GVHD without sacrificing the beneficial graft--leukemia response. BET inhibition reduces T cell alloreactive proliferation, decreases inflammatory cytokine production, and impairs dendritic cell maturation both and . RNA sequencing studies in human T cells revealed that BET inhibition impacts inflammatory IL-17 and IL-12 gene expression signatures, and Chromatin Immunoprecipitation (ChIP)-sequencing revealed that BRD4 binds directly to the IL-23R gene locus. BET inhibition results in decreased IL-23R expression and function as demonstrated by decreased phosphorylation of STAT3 in response to IL-23 stimulation in human T cells as well as in mouse donor T cells . Furthermore, PLX2853 significantly reduced IL-23R+ and pathogenic CD4+ IFNγ+ IL-17+ double positive T cell infiltration in gastrointestinal tissues in an acute GVHD murine model. Our findings identify a role for BET proteins in regulating the IL-23R/STAT3/IL-17 pathway. Based on our preclinical data presented here, PLX51107 will enter clinical trial for refractory acute GVHD in a Phase 1 safety, biological efficacy trial.
急性移植物抗宿主病（GVHD）是异基因造血细胞移植后非复发死亡率的主要原因。大多数对一线类固醇治疗无反应的患者估计总体2年生存率仅为10%。溴结构域和额外末端结构域（BET）蛋白影响炎症基因转录，因此是减轻急性GVHD发病机制核心炎症的潜在靶点。使用强效且选择性的BET抑制剂Plexxikon - 51107和 - 2853（PLX51107和PLX2853），我们发现BET抑制可显著提高急性GVHD小鼠模型的生存率并减少疾病进展，同时不影响有益的移植物抗白血病反应。BET抑制减少T细胞同种异体反应性增殖，降低炎症细胞因子产生，并损害树突状细胞成熟。对人T细胞的RNA测序研究表明，BET抑制影响炎症性白细胞介素 - 17和白细胞介素 - 12基因表达特征，染色质免疫沉淀（ChIP）测序表明BRD4直接结合白细胞介素 - 23受体（IL - 23R）基因位点。BET抑制导致IL - 23R表达和功能降低，这在人T细胞以及小鼠供体T细胞中对IL - 23刺激的反应中，通过信号转导和转录激活因子3（STAT3）磷酸化减少得以证明。此外，在急性GVHD小鼠模型中，PLX2853显著减少胃肠道组织中IL - 23R +和致病性CD4 + IFNγ + IL - 17 +双阳性T细胞浸润。我们的研究结果确定了BET蛋白在调节IL - 23R/STAT3/IL - 17通路中的作用。基于我们在此展示的临床前数据，PLX51107将进入难治性急性GVHD的1期安全性、生物学疗效临床试验。
