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Priming with LSD1 inhibitors promotes the persistence and antitumor effect of adoptively transferred T cells

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Listed:
  • Fengqi Qiu

    (Zhejiang University School of Medicine)

  • Peishan Jiang

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Guiheng Zhang

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Jie An

    (Zhejiang University School of Medicine)

  • Kexin Ruan

    (Zhejiang University School of Medicine)

  • Xiaowen Lyu

    (Xiamen University)

  • Jianya Zhou

    (Zhejiang University School of Medicine)

  • Wanqiang Sheng

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

Abstract

The antitumor efficacy of adoptively transferred T cells is limited by their poor persistence, in part due to exhaustion, but the underlying mechanisms and potential interventions remain underexplored. Here, we show that targeting histone demethylase LSD1 by chemical inhibitors reshapes the epigenome of in vitro activated and expanded CD8+ T cells, and potentiates their antitumor efficacy. Upon T cell receptor activation and IL-2 signaling, a timely and transient inhibition of LSD1 suffices to improve the memory phenotype of mouse CD8+ T cells, associated with a better ability to produce multiple cytokines, resist exhaustion, and persist in both antigen-dependent and -independent manners after adoptive transfer. Consequently, OT1 cells primed with LSD1 inhibitors demonstrate an enhanced antitumor effect in OVA-expressing solid tumor models implanted in female mice, both as a standalone treatment and in combination with PD-1 blockade. Moreover, priming with LSD1 inhibitors promotes polyfunctionality of human CD8+ T cells, and increases the persistence and antitumor efficacy of human CD19-CAR T cells in both leukemia and solid tumor models. Thus, pharmacological inhibition of LSD1 could be exploited to improve adoptive T cell therapy.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48607-4
    DOI: 10.1038/s41467-024-48607-4
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    References listed on IDEAS

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    1. Cheng Zeng & Jiwei Chen & Emmalee W. Cooke & Arijita Subuddhi & Eliana T. Roodman & Fei Xavier Chen & Kaixiang Cao, 2023. "Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Carlson Tsui & Lorenz Kretschmer & Svenja Rapelius & Sarah S. Gabriel & David Chisanga & Konrad Knöpper & Daniel T. Utzschneider & Simone Nüssing & Yang Liao & Teisha Mason & Santiago Valle Torres & S, 2022. "MYB orchestrates T cell exhaustion and response to checkpoint inhibition," Nature, Nature, vol. 609(7926), pages 354-360, September.
    3. Nayan Jain & Zeguo Zhao & Judith Feucht & Richard Koche & Archana Iyer & Anton Dobrin & Jorge Mansilla-Soto & Julie Yang & Yingqian Zhan & Michael Lopez & Gertrude Gunset & Michel Sadelain, 2023. "TET2 guards against unchecked BATF3-induced CAR T cell expansion," Nature, Nature, vol. 615(7951), pages 315-322, March.
    4. Yi Liu & Brian Debo & Mingfeng Li & Zhennan Shi & Wanqiang Sheng & Yang Shi, 2021. "LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    5. 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.
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    Cited by:

    1. Isabella Pallavicini & Teresa Maria Frasconi & Carlotta Catozzi & Elena Ceccacci & Silvia Tiberti & Dorothee Haas & Jule Samson & Christoph Heuser-Loy & Carina B. Nava Lauson & Marta Mangione & Elisa , 2024. "LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8+ T cell responsiveness," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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