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CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells

Author

Listed:
  • Hind Rafei

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Rafet Basar

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Sunil Acharya

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Yu-Sung Hsu

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences)

  • Pinghua Liu

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Deqiang Zhang

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Toszka Bohn

    (University Medical Center of the Johannes Gutenberg University
    University Medical Center
    German Cancer Consortium (DKTK))

  • Qingnan Liang

    (The University of Texas MD Anderson Cancer Center)

  • Vakul Mohanty

    (The University of Texas MD Anderson Cancer Center)

  • Ranjan Upadhyay

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Ping Li

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Pravin Phadatare

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Merve Dede

    (The University of Texas MD Anderson Cancer Center)

  • Donghai Xiong

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Huihui Fan

    (University of Texas Health Science Center at Houston)

  • Corry Mathew Jones

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Sebastian Kunz

    (University Medical Center of the Johannes Gutenberg University)

  • May Daher

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Ana Karen Nunez Cortes

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Mayra Shanley

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Bin Liu

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Sadie Mae Moseley

    (The University of Texas MD Anderson Cancer Center)

  • Chenyu Zhang

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Dexing Fang

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Pinaki Banerjee

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Nadima Uprety

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Ye Li

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Rejeena Shrestha

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Xinhai Wan

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Hong Shen

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Vernikka Woods

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • April Lamour Gilbert

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Seema Rawal

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Jinzhuang Dou

    (The University of Texas MD Anderson Cancer Center)

  • Yukun Tan

    (The University of Texas MD Anderson Cancer Center)

  • Jeong-Min Park

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Francia Reyes Silva

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Alexander Biederstädt

    (The University of Texas MD Anderson Cancer Center
    Technical University of Munich)

  • Mecit Kaplan

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences)

  • Xin Ru Jiang

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences)

  • Inci Biederstädt

    (The University of Texas MD Anderson Cancer Center)

  • Bijender Kumar

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Silvia Tiberti

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Madison Moore

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Jingling Jin

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Ryan Z. Yang

    (The University of Texas MD Anderson Cancer Center)

  • Luis Muniz-Feliciano

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Samuel Rosemore

    (The University of Texas MD Anderson Cancer Center
    University of Maryland)

  • Paul Lin

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Gary M. Deyter

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Natalie Wall Fowlkes

    (The University of Texas MD Anderson Cancer Center)

  • Abhinav K. Jain

    (The University of Texas MD Anderson Cancer Center)

  • David Marin

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Anirban Maitra

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Ken Chen

    (The University of Texas MD Anderson Cancer Center)

  • Tobias Bopp

    (University Medical Center of the Johannes Gutenberg University
    University Medical Center
    German Cancer Consortium (DKTK)
    University Medical Center)

  • Elizabeth J. Shpall

    (The University of Texas MD Anderson Cancer Center)

  • Katayoun Rezvani

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

Abstract

Chimeric antigen receptor (CAR) natural killer (NK) cell immunotherapy offers a promising approach against cancer1–3. However, the molecular mechanisms that regulate CAR-NK cell activity remain unclear. Here we identify the transcription factor cyclic AMP response element modulator (CREM) as a crucial regulator of NK cell function. Transcriptomic analysis revealed a significant induction of CREM in CAR-NK cells during the peak of effector function after adoptive transfer in a tumour mouse model, and this peak coincided with signatures of both activation and dysfunction. We demonstrate that both CAR activation and interleukin-15 signalling rapidly induce CREM upregulation in NK cells. Functionally, CREM deletion enhances CAR-NK cell effector function both in vitro and in vivo and increases resistance to tumour-induced immunosuppression after rechallenge. Mechanistically, we establish that induction of CREM is mediated by the PKA–CREB signalling pathway, which can be activated by immunoreceptor tyrosine-based activation motif signalling downstream of CAR activation or by interleukin-15. Finally, our findings reveal that CREM exerts its regulatory functions through epigenetic reprogramming of CAR-NK cells. Our results provide support for CREM as a therapeutic target to enhance the antitumour efficacy of CAR-NK cells.

Suggested Citation

  • Hind Rafei & Rafet Basar & Sunil Acharya & Yu-Sung Hsu & Pinghua Liu & Deqiang Zhang & Toszka Bohn & Qingnan Liang & Vakul Mohanty & Ranjan Upadhyay & Ping Li & Pravin Phadatare & Merve Dede & Donghai, 2025. "CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells," Nature, Nature, vol. 643(8073), pages 1076-1086, July.
    • Handle: RePEc:nat:nature:v:643:y:2025:i:8073:d:10.1038_s41586-025-09087-8
    DOI: 10.1038/s41586-025-09087-8
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