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

SIMPLE SUMMARY: Our study identified the primary expression of PD-L1 in vascular endothelial cells that correlated with the expression of the mesenchymal markers YKL-40 and Vim and poor patient survival. YKL-40 induced VE-cad expression, which interacted with and upregulated PD-L1, leading to vascular immune escape. In addition, upregulated VE-cad drove CCR5-mediated tumor vascularization. These data may offer solid evidence to decipher molecular mechanisms that contribute to the rigorous resistance of mesenchymal GBM to single anti-immune or angiogenic therapies. Therefore, our findings suggest a novel therapeutic strategy that combines treatments targeting both YKL-40 and VE-cad/or PD-L1 facilitates the blockade of anti-vascular immune evasion and tumor angiogenesis, benefiting patients with mesenchymal GBM. ABSTRACT: 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.