Browsing by Author "Brunory, Abigail"

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    CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10
    (Cell Press, 2020) Guldner, Ian H.; Wang, Qingfei; Yang, Lin; Golomb, Samantha M.; Zhao, Zhuo; Lopez, Jacqueline A.; Brunory, Abigail; Howe, Erin N.; Zhang, Yizhe; Palakurthi, Bhavana; Barron, Martin; Gao, Hongyu; Xuei, Xiaoling; Liu, Yunlong; Li, Jun; Chen, Danny Z.; Landreth, Gary E.; Zhang, Siyuan; Medical and Molecular Genetics, School of Medicine
    Brain 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.