TY - JOUR
T1 - Dura immunity configures leptomeningeal metastasis immunosuppression for cerebrospinal fluid barrier invasion
AU - Zhao, Jiaxu
AU - Zeng, Rui
AU - Li, Xiaohui
AU - Lu, Ying
AU - Wang, Zuoyun
AU - Peng, Haibao
AU - Chen, Hao
AU - Fu, Minjie
AU - Zhang, Ye
AU - Huang, Yang
AU - Chen, Wenhan
AU - Wang, Xin
AU - Guan, Yun
AU - Han, Wei
AU - Huang, Ruofan
AU - Yao, Chengjun
AU - Qin, Zhiyong
AU - Chen, Lingchao
AU - Chen, Liang
AU - Feng, Xue
AU - Yang, Hanting
AU - Pereira, Patrícia M.R.
AU - Tong, Xuemei
AU - Li, Bin
AU - Zhang, Qiangqiang
AU - Chi, Yudan
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85212791677&partnerID=8YFLogxK
U2 - 10.1038/s43018-024-00858-2
DO - 10.1038/s43018-024-00858-2
M3 - Article
C2 - 39710801
AN - SCOPUS:85212791677
SN - 2662-1347
VL - 5
SP - 1940
EP - 1961
JO - Nature Cancer
JF - Nature Cancer
IS - 12
M1 - e20212121
ER -