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

Xudong Wang, Siyu Su, Yuqing Zhu, Xiaolong Cheng, Chen Cheng, Leilei Chen, Anhua Lei, Li Zhang, Yuyan Xu, Dan Ye, Yi Zhang, Wei Li and Jin Zhang ()
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Xudong Wang: Zhejiang University School of Medicine
Siyu Su: Zhejiang University
Yuqing Zhu: Zhejiang University School of Medicine
Xiaolong Cheng: Children’s National Hospital
Chen Cheng: Zhejiang University School of Medicine
Leilei Chen: Shanghai Medical College of Fudan University
Anhua Lei: Zhejiang University School of Medicine
Li Zhang: Zhejiang University School of Medicine
Yuyan Xu: Zhejiang University School of Medicine
Dan Ye: Shanghai Medical College of Fudan University
Yi Zhang: Quanzhou First Hospital Affiliated to Fujian Medical University
Wei Li: Children’s National Hospital
Jin Zhang: Zhejiang University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41470-9

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