Endothelial Rap1B mediates T-cell exclusion to promote tumor growth: a novel mechanism underlying vascular immunosuppression

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE
Guru Prasad Sharma, Ramoji Kosuru, Sribalaji Lakshmikanthan, Shikan Zheng, Yao Chen, Robert Burns, Gang Xin, Weiguo Cui, Magdalena Chrzanowska
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引用次数: 1

Abstract

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.

Abstract Image

内皮Rap1B介导T细胞排斥以促进肿瘤生长:血管免疫抑制的一种新机制。
克服血管免疫抑制:在肿瘤的促血管生成环境中,内皮细胞(EC)对炎症刺激缺乏反应性,这对于癌症免疫疗法的成功至关重要。血管内皮生长因子A(VEGF-A)调节肿瘤EC反应以排除T细胞的机制尚不清楚。在这里,我们证明了先前与正常血管生成有关的小GTP酶Rap1B的EC特异性缺失,限制了内皮特异性Rap1B敲除(Rap1BiΔEC)小鼠的肿瘤生长。EC特异性Rap1B缺失抑制血管生成,但也导致肿瘤微环境的改变,白细胞的募集增加,肿瘤CD8+T细胞的活性增加。CD8+T细胞的耗竭恢复了Rap1BiΔEC小鼠的肿瘤生长。从机制上讲,全局转录组和功能分析表明,在Rap1B缺陷型内皮细胞中,肿瘤细胞因子TNF-α上调信号传导,并增加NF-κB转录。Rap1B缺乏导致TNF-α刺激的内皮细胞中促炎趋化因子和细胞粘附分子(CAMs)表达升高。重要的是,来自Rap1BiΔEC小鼠的肿瘤EC中CAM表达升高。值得注意的是,Rap1B缺失阻止了VEGF-A诱导的CAM表达的免疫抑制下调,表明Rap1B对VEGF-A抑制信号传导至关重要。因此,我们的研究确定了一种新的内皮内源性机制,该机制是内皮细胞对促炎刺激的VEGF-a依赖性脱敏的基础。值得注意的是,他们确定EC Rap1B是癌症免疫疗法中潜在的新血管靶点。
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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
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