气候变化领域集成服务门户(CCPortal): Dynamic chromatin regulatory landscape of human CAR T cell exhaustion

CCPortal

DOI	10.1073/pnas.2104758118
	Dynamic chromatin regulatory landscape of human CAR T cell exhaustion
	Gennert D.G.; Lynn R.C.; Granja J.M.; Weber E.W.; Mumbach M.R.; Zhao Y.; Duren Z.; Sotillo E.; Greenleaf W.J.; Wong W.H.; Satpathy A.T.; Mackall C.L.; Chang H.Y.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:30
英文摘要	Dysfunction in T cells limits the efficacy of cancer immunotherapy. We profiled the epigenome, transcriptome, and enhancer connectome of exhaustion-prone GD2-targeting HA-28z chimeric antigen receptor (CAR) T cells and control CD19-targeting CAR T cells, which present less exhaustion-inducing tonic signaling, at multiple points during their ex vivo expansion. We found widespread, dynamic changes in chromatin accessibility and three-dimensional (3D) chromosome conformation preceding changes in gene expression, notably at loci proximal to exhaustion-associated genes such as PDCD1, CTLA4, and HAVCR2, and increased DNA motif access for AP-1 family transcription factors, which are known to promote exhaustion. Although T cell exhaustion has been studied in detail in mice, we find that the regulatory networks of T cell exhaustion differ between species and involve distinct loci of accessible chromatin and cis-regulated target genes in human CAR T cell exhaustion. Deletion of exhaustion-specific candidate enhancers of PDCD1 suppress the expression of PD-1 in an in vitro model of T cell dysfunction and in HA-28z CAR T cells, suggesting enhancer editing as a path forward in improving cancer immunotherapy. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cancer immunotherapy; Enhancer editing; Epigenomics
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238855
作者单位	Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, United States; Department of Genetics, Stanford University, Stanford, CA 94305, United States; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, United States; Department of Statistics, Stanford University, Stanford, CA 94305, United States; Center for Human Genetics, Department of Genetics and Biochemistry, Clemson University, Greenwood, SC 29646, United States; Department of Applied Physics, Stanford University, Stanford, CA 94305, United States; Chan Zuckerberg Biohub, San Francisco, CA 94158, United States; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, United States; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, United States; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States; HHMI, Stanford University, Stanford, CA 943...
推荐引用方式 GB/T 7714	Gennert D.G.,Lynn R.C.,Granja J.M.,et al. Dynamic chromatin regulatory landscape of human CAR T cell exhaustion[J],2021,118(30).
APA	Gennert D.G..,Lynn R.C..,Granja J.M..,Weber E.W..,Mumbach M.R..,...&Chang H.Y..(2021).Dynamic chromatin regulatory landscape of human CAR T cell exhaustion.Proceedings of the National Academy of Sciences of the United States of America,118(30).
MLA	Gennert D.G.,et al."Dynamic chromatin regulatory landscape of human CAR T cell exhaustion".Proceedings of the National Academy of Sciences of the United States of America 118.30(2021).