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TET2 guards against unchecked BATF3-induced CAR T cell expansion

Author

Listed:
  • Nayan Jain

    (Memorial Sloan Kettering Cancer Centre
    Memorial Sloan Kettering Cancer Centre)

  • Zeguo Zhao

    (Memorial Sloan Kettering Cancer Centre)

  • Judith Feucht

    (Memorial Sloan Kettering Cancer Centre
    University Children’s Hospital)

  • Richard Koche

    (Memorial Sloan Kettering Cancer Centre)

  • Archana Iyer

    (Memorial Sloan Kettering Cancer Centre)

  • Anton Dobrin

    (Memorial Sloan Kettering Cancer Centre
    Memorial Sloan Kettering Cancer Centre)

  • Jorge Mansilla-Soto

    (Memorial Sloan Kettering Cancer Centre)

  • Julie Yang

    (Memorial Sloan Kettering Cancer Centre)

  • Yingqian Zhan

    (Memorial Sloan Kettering Cancer Centre)

  • Michael Lopez

    (Memorial Sloan Kettering Cancer Centre)

  • Gertrude Gunset

    (Memorial Sloan Kettering Cancer Centre)

  • Michel Sadelain

    (Memorial Sloan Kettering Cancer Centre)

Abstract

Further advances in cell engineering are needed to increase the efficacy of chimeric antigen receptor (CAR) and other T cell-based therapies1–5. As T cell differentiation and functional states are associated with distinct epigenetic profiles6,7, we hypothesized that epigenetic programming may provide a means to improve CAR T cell performance. Targeting the gene that encodes the epigenetic regulator ten–eleven translocation 2 (TET2)8 presents an interesting opportunity as its loss may enhance T cell memory9,10, albeit not cause malignancy9,11,12. Here we show that disruption of TET2 enhances T cell-mediated tumour rejection in leukaemia and prostate cancer models. However, loss of TET2 also enables antigen-independent CAR T cell clonal expansions that may eventually result in prominent systemic tissue infiltration. These clonal proliferations require biallelic TET2 disruption and sustained expression of the AP-1 factor BATF3 to drive a MYC-dependent proliferative program. This proliferative state is associated with reduced effector function that differs from both canonical T cell memory13,14 and exhaustion15,16 states, and is prone to the acquisition of secondary somatic mutations, establishing TET2 as a guardian against BATF3-induced CAR T cell proliferation and ensuing genomic instability. Our findings illustrate the potential of epigenetic programming to enhance T cell immunity but highlight the risk of unleashing unchecked proliferative responses.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:615:y:2023:i:7951:d:10.1038_s41586-022-05692-z
    DOI: 10.1038/s41586-022-05692-z
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    Cited by:

    1. 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.

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