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CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10.

Ian H Guldner | Qingfei Wang | Lin Yang | Samantha M Golomb | Zhuo Zhao | Jacqueline A Lopez | Abigail Brunory | Erin N Howe | Yizhe Zhang | Bhavana Palakurthi | Martin Barron | Hongyu Gao | Xiaoling Xuei | Yunlong Liu | Jun Li | Danny Z Chen | Gary E Landreth | Siyuan Zhang
Cell | 2020

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.

Pubmed ID: 33113353 RIS Download

Antibodies used in this publication

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: R01 CA194697
  • Agency: NCI NIH HHS, United States
    Id: R01 CA222405

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