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.

中文翻译：

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对脑转移中的内皮细胞和壁细胞的研究揭示了关键的免疫调节机制

脑转移（BrM）是一种常见的恶性肿瘤，主要起源于肺癌、黑色素瘤和乳腺癌。脉管系统是 BrM 肿瘤微环境的关键组成部分，在调节转移播种和进展中发挥着关键作用。然而，人们对 BrM 血管主要成分（即内皮细胞和壁细胞）的异质性仍然知之甚少。我们对分选的血管细胞类型进行单细胞和批量 RNA 测序，并检测与非肿瘤脑相比在 BrM 中特异富集的多种亚型，包括以前未被识别的免疫调节亚型。我们将人类数据与小鼠模型相结合，创建了一个平台来询问治疗 BrM 的血管靶标。我们发现 BrM 血管系统中的 CD276 免疫检查点分子显着上调，并且抗 CD276 阻断抗体在临床前试验中延长了生存期。这项研究为脉管系统、免疫细胞和癌细胞之间的复杂相互作用提供了重要的见解，对于设计治疗干预措施具有转化意义。