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NKp46 enhances type 1 innate lymphoid cell proliferation and function and anti-acute myeloid leukemia activity

Author

Listed:
  • Rui Ma

    (Sichuan University
    City of Hope National Medical Center)

  • Zhenlong Li

    (City of Hope National Medical Center)

  • Hejun Tang

    (City of Hope National Medical Center)

  • Xiaojin Wu

    (The First Affiliated Hospital of Soochow University)

  • Lei Tian

    (University of California
    University of California)

  • Zahir Shah

    (City of Hope National Medical Center)

  • Ningyuan Liu

    (City of Hope National Medical Center)

  • Tasha Barr

    (City of Hope National Medical Center)

  • Jianying Zhang

    (City of Hope National Medical Center)

  • Sean Wang

    (City of Hope National Medical Center)

  • Srividya Swaminathan

    (City of Hope Beckman Research Institute)

  • Guido Marcucci

    (City of Hope National Medical Center)

  • Yong Peng

    (Sichuan University)

  • Michael A. Caligiuri

    (City of Hope National Medical Center
    City of Hope Beckman Research Institute)

  • Jianhua Yu

    (University of California
    University of California)

Abstract

NKp46 is a critical regulator of natural killer (NK) cell immunity, but its function in non-NK innate immune cells remains unclear. Here, we show that NKp46 is indispensable for expressing IL-2 receptor-α (IL-2Rα) by non-NK liver-resident type-1 innate lymphoid cells (ILC1s). Deletion of NKp46 reduces IL-2Rα on ILC1s by downregulating NF-κB signaling, thus impairing ILC1 proliferation and cytotoxicity in vitro and in vivo. The binding of anti-NKp46 antibody to NKp46 triggers the activation of NF-κB, the expression of IL-2Rα, interferon-γ (IFN-γ), tumor necrosis factor (TNF), proliferation, and cytotoxicity. Functionally, NKp46 expressed on mouse ILC1s interacts with tumor cells through cell–cell contact, increasing ILC1 production of IFN-γ and TNF, and enhancing cytotoxicity. In a mouse model of acute myeloid leukemia, deletion of NKp46 impairs the ability of ILC1s to control tumor growth and reduces survival. This can be reversed by injecting NKp46+ ILC1s into NKp46 knock-out mice. Human NKp46+ ILC1s exhibit stronger cytokine production and cytotoxicity than their NKp46− counterparts, suggesting that NKp46 plays a similar role in humans. These findings identify an NKp46–NF-κB–IL-2Rα axis and suggest that activating NKp46 with an anti-NKp46 antibody may provide a potential strategy for anti-tumor innate immunity.

Suggested Citation

  • Rui Ma & Zhenlong Li & Hejun Tang & Xiaojin Wu & Lei Tian & Zahir Shah & Ningyuan Liu & Tasha Barr & Jianying Zhang & Sean Wang & Srividya Swaminathan & Guido Marcucci & Yong Peng & Michael A. Caligiu, 2025. "NKp46 enhances type 1 innate lymphoid cell proliferation and function and anti-acute myeloid leukemia activity," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55923-w
    DOI: 10.1038/s41467-025-55923-w
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