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

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机构： [1]Center for Molecular Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China. [2]Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA. [3]The First Affiliated Hospital of Soochow University, Suzhou 215005, China. [4]Division of Hematology & Oncology, Department of Medicine, School of Medicine, University of California, Irvine, CA 92697, USA. 5The Clemons Family Center for Transformative Cancer Research, University of California, Irvine, CA 92697, USA. [5]Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA 91010, USA. [6]Division of Transfusion Medicine, City of Hope NationalMedical Center, Los Angeles, CA 91010, USA. [7]Department of Systems Biology,City of Hope Beckman Research Institute, Los Angeles, CA 91010, USA. [8]Gehr Family Center for Leukemia Research, Hematologic Malignancies Research Institute, Department of Hematological Malignancies Translational Science, City of Hope National Medical Center, Los Angeles, CA 91010, USA.

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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.© 2025. The Author(s).

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第一作者：

第一作者机构： [1]Center for Molecular Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China. [2]Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA.

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通讯作者：

通讯机构： [2]Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA. [4]Division of Hematology & Oncology, Department of Medicine, School of Medicine, University of California, Irvine, CA 92697, USA. 5The Clemons Family Center for Transformative Cancer Research, University of California, Irvine, CA 92697, USA. [5]Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA 91010, USA. [8]Gehr Family Center for Leukemia Research, Hematologic Malignancies Research Institute, Department of Hematological Malignancies Translational Science, City of Hope National Medical Center, Los Angeles, CA 91010, USA.

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