CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10.
CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10.
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DOI：
10.1016/j.cell.2020.09.064
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发表时间：
2020-11-25
期刊：
影响因子：
64.5
通讯作者：
Zhang S
中科院分区：
文献类型：
--
作者：
Guldner IH;Wang Q;Yang L;Golomb SM;Zhao Z;Lopez JA;Brunory A;Howe EN;Zhang Y;Palakurthi B;Barron M;Gao H;Xuei X;Liu Y;Li J;Chen DZ;Landreth GE;Zhang S
脑转移瘤（br-met）在免疫学上独特的小生境中发展。中枢神经系统天然髓样细胞（CNS-髓样）和骨髓源性髓样细胞（BMDM）协同调节脑免疫。表型异质性和具体的作用，这些髓细胞亚群在塑造的br-met生态位，以调节br-met生长尚未完全揭示。应用多模式单细胞分析，我们阐明了一个异质的，但空间定义的CNS髓样反应在br-met的生长。我们发现Ccr 2 + BMDM对br-met的影响最小，而CNS-髓样促进br-met的生长。此外，br-met相关的中枢神经系统骨髓表现出Cx 3cr 1的下调。CNS髓系中Cx 3cr 1敲除增加了br-met的发病率，导致干扰素应答信号增强和Cxcl 10上调。值得注意的是，Cxcl 10的中和减少了br-met，而rCxcl 10增加了br-met，并将VISTAHi PD-L1+ CNS-骨髓募集到br-met病变。抑制VISTA和PD-L1信号传导缓解了免疫抑制并降低了br-met负荷。我们的研究结果表明，Cx 3cr 1在CNS髓样细胞的损失触发Cxcl 10介导的恶性循环，培养br-met促进，免疫抑制生态位。在小鼠模型中对脑转移瘤的肿瘤微环境的多模式研究证明了CNS驻留的骨髓细胞群在创造免疫抑制性促转移微环境中的核心作用。
Brain metastasis (br-met) develops in an immunologically-unique br-met niche. Central nervous system-native myeloid cells (CNS-myeloid) and bone marrow-derived myeloid cells (BMDM) cooperatively regulate brain immunity. The phenotypic heterogeneity and specific roles of these myeloid subsets in shaping the br-met niche to regulate br-met outgrowth have not been fully revealed. Applying multimodal single cell analyses, we elucidated a heterogeneous but spatially-defined CNS-myeloid response during br-met outgrowth. We found Ccr2+ BMDM minimally influenced br-met while CNS-myeloid promoted br-met outgrowth. Additionally, br-met-associated CNS-myeloid exhibited downregulation of Cx3cr1. Cx3cr1 knockout in CNS-myeloid increased br-met incidence, leading to an enriched interferon response signature and Cxcl10 upregulation. Significantly, neutralization of Cxcl10 reduced br-met, while rCxcl10 increased br-met and recruited VISTAHi PD-L1+ CNS-myeloid to br-met lesions. Inhibiting VISTA and PD-L1 signaling relieved immune suppression and reduced br-met burden. Our results demonstrate that loss of Cx3cr1 in CNS-myeloid triggers a Cxcl10-mediated vicious cycle, cultivating a br-met-promoting, immune-suppressive niche. A multimodal investigation into the tumor microenvironment of brain metastases in mouse models demonstrates the central role of CNS-resident myeloid populations in creating an immunosuppressive pro-metastatic microenvironment.
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作者：
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