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; Min Luo

doi:10.1038/s41586-023-06511-9

CD300ld on neutrophils is required for tumour-driven immune suppression

Nature. 2023 Sep;621(7980):830-839. doi: 10.1038/s41586-023-06511-9. Epub 2023 Sep 6.

Authors

Chaoxiong Wang^#^{1

2}, Xichen Zheng^#¹, Jinlan Zhang^#³, Xiaoyi Jiang^{1

4}, Jia Wang^{2

5}, Yuwei Li^{1

6}, Xiaonan Li², Guanghui Shen¹, Jiayin Peng², Peixuan Zheng², Yunqing Gu¹, Jiaojiao Chen¹, Moubin Lin⁷, Changwen Deng⁸, Hai Gao⁹, Zhigang Lu^{10

11}, Yun Zhao^{12

13

14}, Min Luo¹⁵

Affiliations

¹ 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, Shanghai, China.
² State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
³ The Fifth People's Hospital of Shanghai, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁴ Zhongshan-Xuhui Hospital of Fudan University, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁵ School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
⁶ Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai Medical College, Fudan University, Shanghai, China.
⁷ Center for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China.
⁸ Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
⁹ Zhongshan-Xuhui Hospital of Fudan University, Institutes of Biomedical Sciences, Fudan University, Shanghai, China. gaohai@fudan.edu.cn.
¹⁰ The Fifth People's Hospital of Shanghai, Institutes of Biomedical Sciences, Fudan University, Shanghai, China. zhiganglu@fudan.edu.cn.
¹¹ Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai Medical College, Fudan University, Shanghai, China. zhiganglu@fudan.edu.cn.
¹² State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. yunzhao@sibcb.ac.cn.
¹³ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. yunzhao@sibcb.ac.cn.
¹⁴ Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. yunzhao@sibcb.ac.cn.
¹⁵ 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, Shanghai, China. luo_min@fudan.edu.cn.

^# Contributed equally.

PMID: 37674079
DOI: 10.1038/s41586-023-06511-9

Abstract

The immune-suppressive tumour microenvironment represents a major obstacle to effective immunotherapy^1,2. 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 resistance^2-4. 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.

MeSH terms

Animals
CRISPR-Cas Systems
Disease Progression
Gene Editing
Humans
Immunotherapy
Lymphocyte Activation
Mice
Myeloid-Derived Suppressor Cells* / immunology
Myeloid-Derived Suppressor Cells* / pathology
Neoplasms* / immunology
Neoplasms* / pathology
Neutrophils* / immunology
Neutrophils* / pathology
Receptors, Immunologic* / immunology
Survival Analysis
T-Lymphocytes / cytology
T-Lymphocytes / immunology
T-Lymphocytes / pathology
Tumor Microenvironment

Substances

CD300LD protein, human
Receptors, Immunologic