CD300ld on neutrophils is required for tumour-driven immune suppression

Chaoxiong Wang, Xichen Zheng, Jinlan Zhang, Xiaoyi Jiang, Jia Wang, Yuwei Li, Xiaonan Li, Guanghui Shen, Jiayin Peng, Peixuan Zheng, Yunqing Gu, Jiaojiao Chen, Moubin Lin, Changwen Deng, Hai Gao (), Zhigang Lu (), Yun Zhao () and Min Luo ()
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Chaoxiong Wang: Institute of Pediatrics of Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Xichen Zheng: Institute of Pediatrics of Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Jinlan Zhang: The Fifth People’s Hospital of Shanghai, Institutes of Biomedical Sciences, Fudan University
Xiaoyi Jiang: Institute of Pediatrics of Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Jia Wang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yuwei Li: Institute of Pediatrics of Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Xiaonan Li: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Guanghui Shen: Institute of Pediatrics of Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Jiayin Peng: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Peixuan Zheng: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yunqing Gu: Institute of Pediatrics of Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Jiaojiao Chen: Institute of Pediatrics of Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Moubin Lin: Yangpu Hospital, School of Medicine, Tongji University
Changwen Deng: Shanghai East Hospital, School of Medicine, Tongji University
Hai Gao: Zhongshan-Xuhui Hospital of Fudan University, Institutes of Biomedical Sciences, Fudan University
Zhigang Lu: The Fifth People’s Hospital of Shanghai, Institutes of Biomedical Sciences, Fudan University
Yun Zhao: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Min Luo: Institute of Pediatrics of Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University

Nature, 2023, vol. 621, issue 7980, 830-839

Abstract: Abstract The immune-suppressive tumour microenvironment represents a major obstacle to effective immunotherapy1,2. Pathologically activated neutrophils, also known as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), are a critical component of the tumour microenvironment and have crucial roles in tumour progression and therapy resistance2–4. Identification of the key molecules on PMN-MDSCs is required to selectively target these cells for tumour treatment. Here, we performed an in vivo CRISPR–Cas9 screen in a tumour mouse model and identified CD300ld as a top candidate of tumour-favouring receptors. CD300ld is specifically expressed in normal neutrophils and is upregulated in PMN-MDSCs upon tumour-bearing. CD300ld knockout inhibits the development of multiple tumour types in a PMN-MDSC–dependent manner. CD300ld is required for the recruitment of PMN-MDSCs into tumours and their function to suppress T cell activation. CD300ld acts via the STAT3-S100A8/A9 axis, and knockout of Cd300ld reverses the tumour immune-suppressive microenvironment. CD300ld is upregulated in human cancers and shows an unfavourable correlation with patient survival. Blocking CD300ld activity inhibits tumour development and has synergistic effects with anti-PD1. Our study identifies CD300ld as a critical immune suppressor present on PMN-MDSCs, being required for tumour immune resistance and providing a potential target for cancer immunotherapy.

Date: 2023
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DOI: 10.1038/s41586-023-06511-9

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