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

Xudong Wang, 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.
Siyu Su, Liangzhu Laboratory, Zhejiang University, Hangzhou, Zhejiang, 311121, China.
Yuqing Zhu, 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.
Xiaolong Cheng, Center for Genetic Medicine Research, Children's National Hospital, 111 Michigan Ave NW, Washington, DC, 20010, USA.
Chen Cheng, 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.
Leilei Chen, 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.
Anhua Lei, 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.
Li Zhang, 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.
Yuyan Xu, 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.
Dan Ye, 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.
Yi Zhang, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, China.
Wei Li, Center for Genetic Medicine Research, Children's National Hospital, 111 Michigan Ave NW, Washington, DC, 20010, USA.
Jin Zhang, 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.

Document Type

Journal Article

Publication Date

9-18-2023

Journal

Nature communications

Volume

14

Issue

1

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.

Department

Genomics and Precision Medicine

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