克服血管免疫抑制——肿瘤血管生成环境中内皮细胞(EC)对炎症刺激缺乏回应是成功的癌症免疫治疗所必需的。血管内皮生长因子A（VEGF-A）调节肿瘤EC响应排除T细胞的机制尚不清楚。我们在这里展示，小型GTP酶Rap1B的内皮特异性删除抑制肿瘤生长，限制内皮细胞特异性Rap1B敲除（Rap1BiΔEC）小鼠中的上皮细胞增生。内皮细胞特异性Rap1B删除抑制了血管生成，但也导致肿瘤微环境的改变，增加了白细胞的招募和肿瘤CD8+ T细胞的活性。去除CD8+ T细胞可恢复Rap1BiΔEC小鼠的肿瘤生长。机制上，全局转录组和功能分析表明，肿瘤细胞因子TNF-α的信号增加了和NF-κB转录，导致Rap1B缺乏的EC。Rap1B缺乏导致TNF-α刺激的EC中proinflammatory趋化因子和细胞黏附分子（CAMs）表达升高。值得注意的是，CAM表达在Rap1BiΔEC小鼠的肿瘤EC中升高。重要的是，Rap1B缺失防止了VEGF-A诱导的免疫抑制性下调CAM表达，证明Rap1B在VEGF-A抑制性信号中是必需的。因此，我们的研究确定了一个新的内皮内源性机制，揭示了VEGF-A依赖的内皮细胞对促炎刺激失灵的机制。值得注意的是，它们将EC Rap1B作为潜在的癌症免疫治疗的新型血管靶点。© 2022作者与施普林格自然属下的排他性许可。

Overcoming vascular immunosuppression: lack of endothelial cell (EC) responsiveness to inflammatory stimuli in the proangiogenic environment of tumors, is essential for successful cancer immunotherapy. The mechanisms through which Vascular Endothelial Growth Factor A(VEGF-A) modulates tumor EC response to exclude T-cells are not well understood. Here, we demonstrate that EC-specific deletion of small GTPase Rap1B, previously implicated in normal angiogenesis, restricts tumor growth in endothelial-specific Rap1B-knockout (Rap1BiΔEC) mice. EC-specific Rap1B deletion inhibits angiogenesis, but also leads to an altered tumor microenvironment with increased recruitment of leukocytes and increased activity of tumor CD8+ T-cells. Depletion of CD8+ T-cells restored tumor growth in Rap1BiΔEC mice. Mechanistically, global transcriptome and functional analyses indicated upregulation of signaling by a tumor cytokine, TNF-α, and increased NF-κB transcription in Rap1B-deficient ECs. Rap1B-deficiency led to elevated proinflammatory chemokine and Cell Adhesion Molecules (CAMs) expression in TNF-α stimulated ECs. Importantly, CAM expression was elevated in tumor ECs from Rap1BiΔEC mice. Significantly, Rap1B deletion prevented VEGF-A-induced immunosuppressive downregulation of CAM expression, demonstrating that Rap1B is essential for VEGF-A-suppressive signaling. Thus, our studies identify a novel endothelial-endogenous mechanism underlying VEGF-A-dependent desensitization of EC to proinflammatory stimuli. Significantly, they identify EC Rap1B as a potential novel vascular target in cancer immunotherapy.© 2022. The Author(s), under exclusive licence to Springer Nature B.V.