文章：

硬脑膜免疫对脑脊液屏障侵袭的免疫抑制作用

Dura immunity configures leptomeningeal metastasis immunosuppression for cerebrospinal fluid barrier invasion 原文发布日期：2024-12-20 

英文摘要：

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. 

摘要翻译：

脑脊液( CSF )屏障上有各种免疫细胞，这些细胞允许周缘细胞免疫监视得以实施。然而，CSF免疫细胞与侵袭性癌细胞之间复杂的相互作用尚不为人所知。我们利用了三重映射、长时距成像和多组学技术，以期探究参与颅膜外转移( Leptomeningeal metastasis, LM )的麦粒状细胞的确切起源、细胞间交叉-talk及其分子图景。从机制角度来看，我们发现，由dura组织来源的LM相关麦粒状细胞(dLAMs)通过依赖性地分泌矩阵金属蛋白酶14(MMP14)，实现了向脑脊液的迁移。进一步的研究表明，dLAMs对于癌细胞中Sphingoproteins 1(SPP1)的分泌具有必要性的依赖关系，这种依赖关系有助于诱导一种免疫抑制的小环境，其中T细胞发生耗竭和失活。相反地，如果能够抑制SPP1与MMP14轴的关系，那么麦粒状细胞将无法绕过屏障，并且能够阻止癌细胞生长，从而改善小鼠模型中LM患者的生存率。我们的发现揭示了存在于颅膜间隙内的一个潜在的非特异免疫源，为CSF屏障功能失调的动态过程提供了见解，并提供了潜在的临床免疫治疗靶点的方向。 

原文链接：

https://www.nature.com/articles/s43018-024-00858-2