文章：

间充质胶质母细胞瘤通过VE-钙黏蛋白与PD-L1的相互作用及调控介导血管免疫逃逸

Vascular Immune Evasion of Mesenchymal Glioblastoma Is Mediated by Interaction and Regulation of VE-Cadherin on PD-L1

原文发布日期：25 August 2023

DOI: 10.3390/cancers15174257

类型: Article

开放获取: 是

英文摘要：

The mesenchymal subtype of glioblastoma (mGBM), which is characterized by rigorous vasculature, resists anti-tumor immune therapy. Here, we investigated the mechanistic link between tumor vascularization and the evasion of immune surveillance. Clinical datasets with GBM transcripts showed that the expression of the mesenchymal markers YKL-40 (CHI3L1) and Vimentin is correlated with elevated expression of PD-L1 and poor disease survival. Interestingly, the expression of PD-L1 was predominantly found in vascular endothelial cells. Orthotopic transplantation of glioma cells GL261 over-expressing YKL-40 in mice showed increased angiogenesis and decreased CD8+ T cell infiltration, resulting in a reduction in mouse survival. The exposure of recombinant YKL-40 protein induced PD-L1 and VE-cadherin (VE-cad) expression in endothelial cells and drove VE-cad-mediated nuclear translocation of β-catenin/LEF, where LEF upregulated PD-L1 expression. YKL-40 stimulated the dissociation of VE-cad from PD-L1, rendering PD-L1 available to interact with PD-1 from CD8+-positive TALL-104 lymphocytes and inhibit TALL-104 cytotoxicity. YKL-40 promoted TALL-104 cell migration and adhesion to endothelial cells via CCR5-dependent chemotaxis but blocked its anti-vascular immunity. Knockdown of VE-cad or the PD-L1 gene ablated the effects of YKL-40 and reinvigorated TALL-104 cell immunity against vessels. In summary, our study demonstrates a novel vascular immune escape mechanism by which mGBM promotes tumor vascularization and malignant transformation.

摘要翻译： 

胶质母细胞瘤的间充质亚型（mGBM）以高度血管化为特征，并对抗肿瘤免疫治疗产生抵抗。本研究探讨了肿瘤血管化与免疫监视逃逸之间的机制联系。对胶质母细胞瘤转录组的临床数据分析显示，间充质标志物YKL-40（CHI3L1）和波形蛋白的表达与PD-L1表达升高及患者不良生存率相关。值得注意的是，PD-L1的表达主要富集于血管内皮细胞。在小鼠脑内移植过表达YKL-40的胶质瘤细胞GL261后，观察到血管生成增加和CD8+ T细胞浸润减少，导致小鼠生存期缩短。重组YKL-40蛋白可诱导内皮细胞表达PD-L1和VE-钙黏蛋白（VE-cad），并驱动VE-cad介导的β-连环蛋白/淋巴增强因子核转位，进而通过淋巴增强因子上调PD-L1表达。YKL-40促使VE-cad与PD-L1解离，使PD-L1得以与CD8+阳性的TALL-104淋巴细胞表面的PD-1结合，从而抑制TALL-104细胞的细胞毒性。通过CCR5依赖性趋化作用，YKL-40促进TALL-104细胞迁移并与内皮细胞粘附，但同时阻断了其抗血管免疫活性。敲低VE-cad或PD-L1基因可消除YKL-40的作用，并恢复TALL-104细胞对血管的免疫攻击能力。总之，本研究揭示了一种新型血管免疫逃逸机制，阐明了间充质亚型胶质母细胞瘤如何通过该机制促进肿瘤血管化和恶性转化。

原文链接：

Vascular Immune Evasion of Mesenchymal Glioblastoma Is Mediated by Interaction and Regulation of VE-Cadherin on PD-L1