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CD300ld on neutrophils is required for tumour-driven immune suppression

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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
    University of Chinese Academy of Sciences, Chinese Academy of Sciences)

  • 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
    Zhongshan-Xuhui Hospital of Fudan University, Institutes of Biomedical Sciences, Fudan University)

  • Jia Wang

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences
    ShanghaiTech University)

  • 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
    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
    Fudan University)

  • Yun Zhao

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences
    ShanghaiTech University
    University of 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)

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.

Suggested Citation

  • 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 &, 2023. "CD300ld on neutrophils is required for tumour-driven immune suppression," Nature, Nature, vol. 621(7980), pages 830-839, September.
    • Handle: RePEc:nat:nature:v:621:y:2023:i:7980:d:10.1038_s41586-023-06511-9
    DOI: 10.1038/s41586-023-06511-9
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    Cited by:

    1. Hao Li & Zebei Han & Yu Sun & Fu Wang & Pengzhen Hu & Yuang Gao & Xuemei Bai & Shiyu Peng & Chao Ren & Xiang Xu & Zeyu Liu & Hebing Chen & Yang Yang & Xiaochen Bo, 2024. "CGMega: explainable graph neural network framework with attention mechanisms for cancer gene module dissection," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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