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

Author

Listed:
  • Yao Wang

    (Chinese People’s Liberation Army General Hospital
    Chinese People’s Liberation Army General Hospital)

  • Chuan Tong

    (Chinese People’s Liberation Army General Hospital)

  • Hanren Dai

    (Chinese People’s Liberation Army General Hospital)

  • Zhiqiang Wu

    (Chinese People’s Liberation Army General Hospital)

  • Xiao Han

    (Chinese People’s Liberation Army General Hospital)

  • Yelei Guo

    (Chinese People’s Liberation Army General Hospital)

  • Deyun Chen

    (Chinese People’s Liberation Army General Hospital)

  • Jianshu Wei

    (Chinese People’s Liberation Army General Hospital)

  • Dongdong Ti

    (Chinese People’s Liberation Army General Hospital)

  • Zongzhi Liu

    (Beijing Institute of Genomics, Chinese Academy of Sciences)

  • Qian Mei

    (Chinese People’s Liberation Army General Hospital)

  • Xiang Li

    (Chinese People’s Liberation Army General Hospital)

  • Liang Dong

    (Chinese People’s Liberation Army General Hospital)

  • Jing Nie

    (Chinese People’s Liberation Army General Hospital)

  • Yajing Zhang

    (Chinese People’s Liberation Army General Hospital)

  • Weidong Han

    (Chinese People’s Liberation Army General Hospital
    Chinese People’s Liberation Army General Hospital)

Abstract

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.

Suggested Citation

  • Yao Wang & Chuan Tong & Hanren Dai & Zhiqiang Wu & Xiao Han & Yelei Guo & Deyun Chen & Jianshu Wei & Dongdong Ti & Zongzhi Liu & Qian Mei & Xiang Li & Liang Dong & Jing Nie & Yajing Zhang & Weidong Ha, 2021. "Low-dose decitabine priming endows CAR T cells with enhanced and persistent antitumour potential via epigenetic reprogramming," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20696-x
    DOI: 10.1038/s41467-020-20696-x
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    Cited by:

    1. Bihui Cao & Manting Liu & Lu Wang & Kangshun Zhu & Mingyue Cai & Xiaopei Chen & Yunfei Feng & Shuo Yang & Shengyu Fu & Cheng Zhi & Xiaodie Ye & Jian Zhang & Zhiru Zhang & Xin Yang & Ming Zhao & Qingde, 2022. "Remodelling of tumour microenvironment by microwave ablation potentiates immunotherapy of AXL-specific CAR T cells against non-small cell lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Vipul Bhatia & Nikhil V. Kamat & Tiffany E. Pariva & Li-Ting Wu & Annabelle Tsao & Koichi Sasaki & Huiyun Sun & Gerardo Javier & Sam Nutt & Ilsa Coleman & Lauren Hitchcock & Ailin Zhang & Dmytro Rudoy, 2023. "Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    3. Fengqi Qiu & Peishan Jiang & Guiheng Zhang & Jie An & Kexin Ruan & Xiaowen Lyu & Jianya Zhou & Wanqiang Sheng, 2024. "Priming with LSD1 inhibitors promotes the persistence and antitumor effect of adoptively transferred T cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Maxine S. Y. Lam & Jose Antonio Reales-Calderon & Jin Rong Ow & Joey J. Y. Aw & Damien Tan & Ragavi Vijayakumar & Erica Ceccarello & Tommaso Tabaglio & Yan Ting Lim & Wang Loo Chien & Fritz Lai & Anth, 2023. "G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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