2. Academic Validation
  3. Venetoclax acts as an immunometabolic modulator to potentiate adoptive NK cell immunotherapy against leukemia

Venetoclax acts as an immunometabolic modulator to potentiate adoptive NK cell immunotherapy against leukemia

  • Cell Rep Med. 2024 May 21:101580. doi: 10.1016/j.xcrm.2024.101580.
Yan Wang 1,  Beibei Huang 2,  Tingting Liang 1,  Lai Jiang 3,  Mingming Wu 1,  Xinru Liu 1,  Mingming Zhu 1,  Xian Song 1,  Na Zhao 4,  Haiming Wei 5,  Changcheng Zheng 6,  Fang Ni 7
Affiliations

Affiliations

  • 1 Department of Hematology, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Institute of Immunology, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 2 Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 3 Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 4 Department of Hematology, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 5 Department of Hematology, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Institute of Immunology, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. Electronic address: ustcwhm@ustc.edu.cn.
  • 6 Department of Hematology, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. Electronic address: zhengchch1123@ustc.edu.cn.
  • 7 Department of Hematology, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Institute of Immunology, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. Electronic address: fangni@ustc.edu.cn.
PMID: 38776913 DOI: 10.1016/j.xcrm.2024.101580
Abstract

Natural killer (NK) cell-based immunotherapy holds promise for Cancer treatment; however, its efficacy remains limited, necessitating the development of alternative strategies. Here, we report that venetoclax, an FDA-approved Bcl-2 Inhibitor, directly activates NK cells, enhancing their cytotoxicity against acute myeloid leukemia (AML) both in vitro and in vivo, likely independent of Bcl-2 inhibition. Through comprehensive approaches, including bulk and single-cell RNA Sequencing, avidity measurement, and functional assays, we demonstrate that venetoclax increases the avidity of NK cells to AML cells and promotes lytic granule polarization during immunological synapse (IS) formation. Notably, we identify a distinct CD161lowCD218b+ NK cell subpopulation that exhibits remarkable sensitivity to venetoclax treatment. Furthermore, venetoclax promotes mitochondrial respiration and ATP synthesis via the NF-κB pathway, thereby facilitating IS formation in NK cells. Collectively, our findings establish venetoclax as a multifaceted immunometabolic modulator of NK cell function and provide a promising strategy for augmenting NK cell-based Cancer Immunotherapy.

Keywords

NF-κB; RNA sequencing; acute myeloid leukemia; avidity; cytotoxicity; immunological synapse; immunotherapy; mitochondrial respiration; natural killer cells; venetoclax.

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