Interrogation of endothelial and mural cells in brain metastasis reveals key immune-regulatory mechanisms.

Brain metastasis (BrM) is a common malignancy, predominantly originating from lung, melanoma, and breast cancers. The vasculature is a key component of the BrM tumor microenvironment with critical roles in regulating metastatic seeding and progression. However, the heterogeneity of the major BrM vascular components, namely endothelial and mural cells, is still poorly understood. We perform single-cell and bulk RNA-sequencing of sorted vascular cell types and detect multiple subtypes enriched specifically in BrM compared to non-tumor brain, including previously unrecognized immune regulatory subtypes. We integrate the human data with mouse models, creating a platform to interrogate vascular targets for the treatment of BrM. We find that the CD276 immune checkpoint molecule is significantly upregulated in the BrM vasculature, and anti-CD276 blocking antibodies prolonged survival in preclinical trials. This study provides important insights into the complex interactions between the vasculature, immune cells, and cancer cells, with translational relevance for designing therapeutic interventions. [Display omitted] • We performed single-cell and bulk RNA-seq of human BrM and healthy brain vascular cells • BrMs are defined by pathological endothelial and mural cell subtypes • We created a preclinical platform by integrating human data with mouse BrM models • This interspecies analysis revealed CD276 as a potential therapeutic target for BrM The brain tumor-associated vasculature is a key component of the tumor microenvironment in brain metastasis, protecting cancer cells from immune attack and interfering with the delivery of therapeutic agents into the brain. In this study, Bejarano et al. unravel the vascular heterogeneity in human BrM and further construct a preclinical platform to design novel vascular-targeted therapeutic strategies for the treatment of these aggressive tumors. [ABSTRACT FROM AUTHOR]