Low-dose decitabine priming endows CAR T cells with enhanced and persistent antitumour potential via epigenetic reprogramming

Insufficient eradication capacity and dysfunction are common occurrences in T cells that characterize cancer immunotherapy failure. De novo DNA methylation promotes T cell exhaustion, whereas methylation inhibition enhances T cell rejuvenation in vivo. Decitabine, a DNA methyltransferase inhibitor a...

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Vydáno v:	Nature communications Ročník 12; číslo 1; s. 409 - 18
Hlavní autoři:	Wang, Yao, Tong, Chuan, Dai, Hanren, Wu, Zhiqiang, Han, Xiao, Guo, Yelei, Chen, Deyun, Wei, Jianshu, Ti, Dongdong, Liu, Zongzhi, Mei, Qian, Li, Xiang, Dong, Liang, Nie, Jing, Zhang, Yajing, Han, Weidong
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 18.01.2021 Nature Publishing Group Nature Portfolio
Témata:	101/1 13/1 13/2 13/21 13/31 13/51 14/32 38/23 38/91 5-aza-2'-deoxycytidine 631/67/1059/2325 64/60 692/308/575 Animals Anticancer properties Antigens Cancer Cancer immunotherapy CD19 antigen Cell Culture Techniques - methods Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Cell Proliferation - genetics Chimeric antigen receptors Cytokines Cytokines - genetics Cytokines - immunology Decitabine - pharmacology Deoxyribonucleic acid DNA DNA methylation DNA Methylation - drug effects DNA methyltransferase Dose-Response Relationship, Drug Epigenesis, Genetic - drug effects Epigenesis, Genetic - immunology Epigenetics Female Gene expression Gene Expression Regulation, Neoplastic - drug effects Gene Expression Regulation, Neoplastic - immunology Genes Humanities and Social Sciences Humans Immunological memory Immunotherapy Immunotherapy, Adoptive - methods Inhibitors Lymphocytes Lymphocytes T Lymphocytes, Tumor-Infiltrating - immunology Memory cells Mice multidisciplinary Neoplasms - blood Neoplasms - immunology Neoplasms - pathology Neoplasms - therapy Pretreatment Priming Receptors, Chimeric Antigen - immunology RNA-Seq Science Science (multidisciplinary) T-Lymphocytes - drug effects T-Lymphocytes - immunology T-Lymphocytes - transplantation Tumors Xenograft Model Antitumor Assays
ISSN:	2041-1723, 2041-1723
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Shrnutí:	Insufficient eradication capacity and dysfunction are common occurrences in T cells that characterize cancer immunotherapy failure. De novo DNA methylation promotes T cell exhaustion, whereas methylation inhibition enhances T cell rejuvenation in vivo. Decitabine, a DNA methyltransferase inhibitor approved for clinical use, may provide a means of modifying exhaustion-associated DNA methylation programmes. Herein, anti-tumour activities, cytokine production, and proliferation are enhanced in decitabine-treated chimeric antigen receptor T (dCAR T) cells both in vitro and in vivo. Additionally, dCAR T cells can eradicate bulky tumours at a low-dose and establish effective recall responses upon tumour rechallenge. Antigen-expressing tumour cells trigger higher expression levels of memory-, proliferation- and cytokine production-associated genes in dCAR T cells. Tumour-infiltrating dCAR T cells retain a relatively high expression of memory-related genes and low expression of exhaustion-related genes in vivo. In vitro administration of decitabine may represent an option for the generation of CAR T cells with improved anti-tumour properties. De novo DNA methylation has been associated with T cell exhaustion in cancer immunotherapy. Here the authors show that the pre-treatment of CD19 CAR-T cells with the DNA methyltransferase inhibitor decitabine limits exhaustion and confers enhanced proliferative, effector and memory properties upon antigen exposure, with improved tumor control.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Undefined-3
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-020-20696-x