2. Academic Validation
  3. Metabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophages in solid tumors

Metabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophages in solid tumors

  • Nat Commun. 2023 Sep 18;14(1):5778. doi: 10.1038/s41467-023-41470-9.
Xudong Wang # 1 2,  Siyu Su # 2 3,  Yuqing Zhu 1 4,  Xiaolong Cheng 5 6,  Chen Cheng 1,  Leilei Chen 7,  Anhua Lei 1 8,  Li Zhang 1,  Yuyan Xu 1,  Dan Ye 7 9,  Yi Zhang 3,  Wei Li 5 6,  Jin Zhang 10 11 12 13
Affiliations

Affiliations

  • 1 Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
  • 2 Liangzhu Laboratory, Zhejiang University, Hangzhou, Zhejiang, 311121, China.
  • 3 Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, China.
  • 4 Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei, Anhui, 230601, China.
  • 5 Center for Genetic Medicine Research, Children's National Hospital, 111 Michigan Ave NW, Washington, DC, 20010, USA.
  • 6 Department of Genomics and Precision Medicine, George Washington University, 111 Michigan Ave NW, Washington, DC, 20010, USA.
  • 7 Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, Huadong Hospital, and Shanghai Key laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, China.
  • 8 CellOrigin Inc, Hangzhou, 310000, China.
  • 9 Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
  • 10 Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China. zhgene@zju.edu.cn.
  • 11 Liangzhu Laboratory, Zhejiang University, Hangzhou, Zhejiang, 311121, China. zhgene@zju.edu.cn.
  • 12 Institute of Hematology, Zhejiang University, Hangzhou, 310058, China. zhgene@zju.edu.cn.
  • 13 Center of Gene/Cell Engineering and Genome Medicine of Zhejiang Province, Hangzhou, 310000, China. zhgene@zju.edu.cn.
  • # Contributed equally.
PMID: 37723178 DOI: 10.1038/s41467-023-41470-9
Abstract

The pro-inflammatory state of macrophages, underpinned by their metabolic condition, is essentially affecting their capacity of combating tumor cells. Here we find, via a pooled metabolic gene knockout CRISPR screen that KEAP1 and ACOD1 are strong regulators of the pro-inflammatory state in macrophages. We show that ACOD1 knockout macrophages, generated in our induced pluripotent stem cell-derived CAR-macrophage (CAR-iMAC) platform, are strongly and persistently polarized toward the pro-inflammatory state, which manifests in increased Reactive Oxygen Species (ROS) production, more potent phagocytosis and enhanced cytotoxic functions against Cancer cells in vitro. In ovarian or pancreatic Cancer mouse models, ACOD1-depleted CAR-iMACs exhibit enhanced capacity in repressing tumors, leading to increased survival. In addition, combining ACOD1-depleted CAR-iMACs with immune checkpoint inhibitors (ICI), such as anti-CD47 or anti-PD1 Antibodies, result in even stronger tumor suppressing effect. Mechanistically, the depletion of ACOD1 reduces levels of the immuno-metabolite itaconate, allowing KEAP1 to prevent NRF2 from entering the nucleus to activate an anti-inflammatory program. This study thus lays down the proof of principle for targeting ACOD1 in myeloid cells for Cancer Immunotherapy and introduces metabolically engineered human iPSC-derived CAR-iMACs cells with enhanced polarization and anti-tumor functions in adoptive cell transfer therapies.

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