Dura immunity configures leptomeningeal metastasis immunosuppression for cerebrospinal fluid barrier invasion

Jiaxu Zhao; Rui Zeng; Xiaohui Li; Ying Lu; Zuoyun Wang; Haibao Peng; Hao Chen; Minjie Fu; Ye Zhang; Yang Huang; Wenhan Chen; Xin Wang; Yun Guan; Wei Han; Ruofan Huang; Chengjun Yao; Zhiyong Qin; Lingchao Chen; Liang Chen; Xue Feng; Hanting Yang; Patrícia M R Pereira; Xuemei Tong; Bin Li; Qiangqiang Zhang; Yudan Chi

doi:10.1038/s43018-024-00858-2

Dura immunity configures leptomeningeal metastasis immunosuppression for cerebrospinal fluid barrier invasion

Nat Cancer. 2024 Dec;5(12):1940-1961. doi: 10.1038/s43018-024-00858-2. Epub 2024 Dec 20.

Authors

Jiaxu Zhao^#^{1

2

3

4

5}, Rui Zeng^#^{1

2

3

4

5}, Xiaohui Li^{1

2

3

4

5}, Ying Lu^{6

7}, Zuoyun Wang^{8

9}, Haibao Peng^{1

2

3

4

5}, Hao Chen^{2

3

4

5}, Minjie Fu¹, Ye Zhang^{1

2

3

4

5}, Yang Huang^{1

2

3

4

5}, Wenhan Chen^{2

3

4

5}, Xin Wang^{10

11

12

13}, Yun Guan^{10

11

12

13}, Wei Han¹, Ruofan Huang¹⁴, Chengjun Yao¹, Zhiyong Qin¹, Lingchao Chen¹, Liang Chen¹, Xue Feng¹⁵, Hanting Yang^{2

16}, Patrícia M R Pereira¹⁷, Xuemei Tong^{18

19

20}, Bin Li^{21

22}, Qiangqiang Zhang^{23

24}, Yudan Chi^{25

26

27

28

29}

Affiliations

¹ Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
² Institute for Translational Brain Research, Fudan University, Shanghai, China.
³ State Key Laboratory of Medical Neurobiology, Shanghai, China.
⁴ MOE Frontiers Center for Brain Science, Shanghai, China.
⁵ MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Shanghai, China.
⁶ Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Shanghai, China.
⁷ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
⁸ Department of Anatomy and Histoembryology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
⁹ Department of Gastroenterology, Shanghai Xuhui Center Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
¹⁰ CyberKnife Center, Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
¹¹ Neurosurgical Institute, Fudan University, Shanghai, China.
¹² National Center for Neurological Disorders, Shanghai, China.
¹³ Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China.
¹⁴ Department of Oncology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
¹⁵ Laboratory Animal Center, Fudan University, Shanghai, China.
¹⁶ Department of Neurology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
¹⁷ Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
¹⁸ Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹⁹ Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai, China.
²⁰ Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai, China.
²¹ Center for Immune-Related Diseases at Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
²² Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
²³ Advanced Model Animal Research Center, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Zhejiang, China. [email protected].
²⁴ Zhejiang Key Laboratory of Multiomics and Molecular Enzymology, Yangtze Delta Region Institute of Tsinghua University, Zhejiang, China. [email protected].
²⁵ Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
²⁶ Institute for Translational Brain Research, Fudan University, Shanghai, China. [email protected].
²⁷ State Key Laboratory of Medical Neurobiology, Shanghai, China. [email protected].
²⁸ MOE Frontiers Center for Brain Science, Shanghai, China. [email protected].
²⁹ MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Shanghai, China. [email protected].

^# Contributed equally.

PMID: 39710801
DOI: 10.1038/s43018-024-00858-2

Abstract

The cerebrospinal fluid (CSF) border accommodates diverse immune cells that permit peripheral cell immunosurveillance. However, the intricate interactions between CSF immune cells and infiltrating cancer cells remain poorly understood. Here we use fate mapping, longitudinal time-lapse imaging and multiomics technologies to investigate the precise origin, cellular crosstalk and molecular landscape of macrophages that contribute to leptomeningeal metastasis (LM) progression. Mechanically, we find that dura-derived LM-associated macrophages (dLAMs) migrate into the CSF in a matrix metalloproteinase 14 (MMP14)-dependent manner. Furthermore, we identify that dLAMs critically require the presence of secreted phosphoprotein 1 (SPP1) in cancer cells for their recruitment, fostering an immunosuppressed microenvironment characterized by T cell exhaustion and inactivation. Conversely, inhibition of the SPP1-MMP14 axis can impede macrophages from bypassing the border barrier, prevent cancer cell growth and improve survival in LM mouse models. Our findings reveal an unexpectedly private source of innate immunity within the meningeal space, shed light on CSF barrier dysfunction dynamics and supply potential targets of clinical immunotherapy.

MeSH terms

Animals
Cell Line, Tumor
Cell Movement
Cerebrospinal Fluid / cytology
Cerebrospinal Fluid / immunology
Dura Mater* / immunology
Female
Humans
Immune Tolerance
Immunity, Innate
Macrophages / immunology
Matrix Metalloproteinase 14
Meningeal Neoplasms / cerebrospinal fluid
Meningeal Neoplasms / immunology
Meningeal Neoplasms / secondary
Mice
Osteopontin / cerebrospinal fluid
Tumor Microenvironment* / immunology

Substances

Matrix Metalloproteinase 14
Osteopontin

Abstract

MeSH terms

Substances

Grants and funding