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

Cell. 2020 Nov 25;183(5):1234-1248.e25. doi: 10.1016/j.cell.2020.09.064. Epub 2020 Oct 27.


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.

Keywords: Brain metastasis; T cells; bone marrow-derived myeloid cells; brain immunity; cancer immunology; immune suppression; immune therapy; metastatic niche; microglia; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bone Marrow Cells / metabolism
  • Brain Neoplasms / genetics
  • Brain Neoplasms / immunology*
  • Brain Neoplasms / pathology
  • Brain Neoplasms / secondary*
  • CX3C Chemokine Receptor 1 / metabolism
  • Central Nervous System / pathology
  • Chemokine CXCL10 / metabolism*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunosuppression Therapy*
  • Interferons / metabolism
  • Macrophages / metabolism
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells / metabolism*
  • Neutralization Tests
  • Phenotype
  • T-Lymphocytes / immunology
  • Transcriptome / genetics


  • CX3C Chemokine Receptor 1
  • Chemokine CXCL10
  • Cx3cr1 protein, mouse
  • Membrane Proteins
  • Vsir protein, mouse
  • Interferons