Transmural Flow Upregulates PD-L1 Expression in Microvascular Networks.
Transmural Flow Upregulates PD-L1 Expression in Microvascular Networks.
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DOI：
10.1002/advs.202400921
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发表时间：
2024-05
期刊：
影响因子：
15.1
通讯作者：
Zhengpeng Wan;Shun Zhang;Amy X Zhong;Liling Xu;M. F. Coughlin;Georgios Pavlou;Sarah E Shelton
中科院分区：
文献类型：
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作者：
Zhengpeng Wan;Shun Zhang;Amy X Zhong;Liling Xu;M. F. Coughlin;Georgios Pavlou;Sarah E Shelton
内皮细胞程序性死亡配体1（PD-L1）在肿瘤中的表达高于正常组织。此外，肿瘤血管往往比正常血管更易渗漏，导致更高的跨内皮或透壁流体流动。然而，尚不清楚这种升高的透壁血流是否可以控制内皮PD-L1表达。在这里，开发了一种新的微流体装置来研究微血管网络（MVNs）中透壁流动和PD-L1表达之间的关系。用透壁血流处理MVN 24 h后，内皮细胞中PD-L1的表达上调。此外，当在用透壁流预处理的MVN中培养时，植物血凝素（PHA）对CD 8 T细胞的活化被抑制。此外，透壁流动能够进一步增加肿瘤微环境中形成的血管中的PD-L1表达。最后，通过利用阻断抗体和敲除试验，发现跨壁流动驱动的PD-L1上调受整合素αVβ3控制。总的来说，这项研究为肿瘤血管中PD-L1的高表达提供了新的生物物理学解释。
Endothelial programmed death-ligand 1 (PD-L1) expression is higher in tumors than in normal tissues. Also, tumoral vasculatures tend to be leakier than normal vessels leading to a higher trans-endothelial or transmural fluid flow. However, it is not clear whether such elevated transmural flow can control endothelial PD-L1 expression. Here, a new microfluidic device is developed to investigate the relationship between transmural flow and PD-L1 expression in microvascular networks (MVNs). After treating the MVNs with transmural flow for 24 h, the expression of PD-L1 in endothelial cells is upregulated. Additionally, CD8 T cell activation by phytohemagglutinin (PHA) is suppressed when cultured in the MVNs pre-conditioned with transmural flow. Moreover, transmural flow is able to further increase PD-L1 expression in the vessels formed in the tumor microenvironment. Finally, by utilizing blocking antibodies and knock-out assays, it is found that transmural flow-driven PD-L1 upregulation is controlled by integrin αVβ3. Overall, this study provides a new biophysical explanation for high PD-L1 expression in tumoral vasculatures.