Guldner, Ian H.Wang, QingfeiYang, LinGolomb, Samantha M.Zhao, ZhuoLopez, Jacqueline A.Brunory, AbigailHowe, Erin N.Zhang, YizhePalakurthi, BhavanaBarron, MartinGao, HongyuXuei, XiaolingLiu, YunlongLi, JunChen, Danny Z.Landreth, Gary E.Zhang, Siyuan2023-03-292023-03-292020Guldner IH, Wang Q, Yang L, et al. CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10. Cell. 2020;183(5):1234-1248.e25. doi:10.1016/j.cell.2020.09.064https://hdl.handle.net/1805/32115Brain metastasis (br-met) develops in an immunologically unique br-met niche. Central nervous system-native myeloid cells (CNS-myeloids) and bone-marrow-derived myeloid cells (BMDMs) 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+ BMDMs 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.en-USPublisher PolicyBrain metastasisT cellsBone marrow-derived myeloid cellsBrain immunityCancer immunologyImmune suppressionImmune therapyMetastatic nicheMicrogliaTumor microenvironmentArticle