气候变化领域集成服务门户(CCPortal): Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling

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DOI	10.1126/science.aba1786
	Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling
	Weber E.W.; Parker K.R.; Sotillo E.; Lynn R.C.; Anbunathan H.; Lattin J.; Good Z.; Belk J.A.; Daniel B.; Klysz D.; Malipatlolla M.; Xu P.; Bashti M.; Heitzeneder S.; Labanieh L.; Vandris P.; Majzner R.G.; Qi Y.; Sandor K.; Chen L.-C.; Prabhu S.; Gentles A.J.; Wandless T.J.; Satpathy A.T.; Chang H.Y.; Mackall C.L.
发表日期	2021
ISSN	0036-8075
卷号	372 期号:6537
英文摘要	T cell exhaustion limits immune responses against cancer and is a major cause of resistance to chimeric antigen receptor (CAR)-T cell therapeutics. Using murine xenograft models and an in vitro model wherein tonic CAR signaling induces hallmark features of exhaustion, we tested the effect of transient cessation of receptor signaling, or rest, on the development and maintenance of exhaustion. Induction of rest through enforced down-regulation of the CAR protein using a drug-regulatable system or treatment with the multikinase inhibitor dasatinib resulted in the acquisition of a memory-like phenotype, global transcriptional and epigenetic reprogramming, and restored antitumor functionality in exhausted CAR-T cells. This work demonstrates that rest can enhance CAR-T cell efficacy by preventing or reversing exhaustion, and it challenges the notion that exhaustion is an epigenetically fixed state. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
英文关键词	dasatinib; lymphoid enhancer factor 1; protein TOX; T lymphocyte receptor; transcription factor; transcription factor 7; transcription factor EZH2; transcriptome; unclassified drug; dasatinib; EZH2 protein, human; hepatocyte nuclear factor 1alpha; high mobility group protein; HNF1A protein, human; LEF1 protein, human; lymphoid enhancer factor 1; TOX protein, human; transcription factor EZH2; antigen; cancer; cell; enzyme; enzyme activity; inhibitor; phenotype; protein; tumor; adoptive transfer; animal experiment; animal model; Article; cell fate; cell function; cell population; cell proliferation; cell regeneration; cell survival; controlled study; epigenetics; ex vivo study; female; gene expression regulation; genetic transcription; human; human cell; in vitro study; in vivo study; male; memory T lymphocyte; mouse; multiomics; nonhuman; nuclear reprogramming; osteosarcoma; osteosarcoma cell line; phenotype; priority journal; signal transduction; single cell analysis; tumor volume; tumor xenograft; upregulation; adoptive immunotherapy; animal; chemistry; cytotoxicity; down regulation; drug screening; experimental neoplasm; genetic epigenesis; immunological memory; immunology; lymphocyte activation; metabolism; protein domain; protein stability; T lymphocyte; tumor cell line; Murinae; Animals; Cell Line, Tumor; Cytotoxicity, Immunologic; Dasatinib; Down-Regulation; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Epigenome; Female; Hepatocyte Nuclear Factor 1-alpha; High Mobility Group Proteins; Humans; Immunologic Memory; Immunotherapy, Adoptive; Lymphocyte Activation; Lymphoid Enhancer-Binding Factor 1; Male; Mice; Neoplasms, Experimental; Protein Domains; Protein Stability; Receptors, Chimeric Antigen; Signal Transduction; T-Lymphocytes; Transcription, Genetic; Xenograft Model Antitumor Assays
语种	英语
来源期刊	Science
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/245983
作者单位	Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, School of Medicine, Stanford, CA 94305, United States; Department of Personal Dynamic Regulomes, Stanford University, School of Medicine, Stanford, CA 94305, United States; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, United States; Department of Biomedical Data Science, Stanford University, School of Medicine, Stanford, CA 94305, United States; Department of Computer Science, Stanford University, Stanford, CA 94305, United States; Department of Pathology, Stanford University, Stanford, CA 94305, United States; Department of Pediatrics, Stanford University, School of Medicine, Stanford, CA 94305, United States; Department of Chemical and Systems Biology, Stanford UniversityCA 94305, United States; Department of Biomedical Informatics Research, Stanford University, School of Medicine, Stanford, CA 94305, United States; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, Uni...
推荐引用方式 GB/T 7714	Weber E.W.,Parker K.R.,Sotillo E.,et al. Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling[J],2021,372(6537).
APA	Weber E.W..,Parker K.R..,Sotillo E..,Lynn R.C..,Anbunathan H..,...&Mackall C.L..(2021).Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling.Science,372(6537).
MLA	Weber E.W.,et al."Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling".Science 372.6537(2021).