Glioblastoma (GBM) is a non-T-cell-inflamed cancer characterized by an immunosuppressive microenvironment that impedes dendritic cell maturation and T-cell cytotoxicity. Proangiogenic cytokines such as VEGF and angiopoietin-2 (Ang-2) have high expression in glioblastoma in a cell-specific manner and not only drive tumor angiogenesis and vascular permeability but also negatively regulate T-lymphocyte and innate immune cell responses. Consequently, the alleviation of immunosuppression might be a prerequisite for successful immune checkpoint therapy in GBM. We here combined antiangiogenic and immune checkpoint therapy and demonstrated improved therapeutic efficacy in syngeneic, orthotopic GBM models. We observed that blockade of VEGF, Ang-2, and programmed cell death protein-1 (PD-1) significantly extended survival compared with vascular targeting alone. In the GBM microenvironment, triple therapy increased the numbers of CTLs, which inversely correlated with myeloid-derived suppressor cells and regulatory T cells. Transcriptome analysis of GBM microvessels indicated a global vascular normalization that was highest after triple therapy. Our results propose a rationale to overcome tumor immunosuppression and the current limitations of VEGF monotherapy by integrating the synergistic effects of VEGF/Ang-2 and PD-1 blockade to reinforce antitumor immunity through a normalized vasculature.

中文翻译：

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胶质母细胞瘤中的肿瘤血管正常化，免疫刺激性重新编程和生存改善，同时具有PD-1，Angiopoietin-2和VEGF的联合抑制作用。

胶质母细胞瘤（GBM）是非T细胞发炎的癌症，其特征在于具有免疫抑制性微环境，可阻止树突状细胞成熟和T细胞细胞毒性。促血管生成细胞因子，例如VEGF和血管生成素2（Ang-2）在胶质母细胞瘤中以细胞特异性方式高表达，不仅驱动肿瘤血管生成和血管通透性，而且对T淋巴细胞和先天免疫细胞反应产生负调节作用。因此，减轻免疫抑制可能是GBM中成功进行免疫检查点治疗的先决条件。我们在这里结合了抗血管生成和免疫检查点疗法，并证明了在同基因原位GBM模型中改善的治疗功效。我们观察到VEGF，Ang-2，与单独的血管靶向治疗相比，程序性细胞死亡蛋白1（PD-1）可以显着延长生存期。在GBM微环境中，三联疗法增加了CTL的数量，而CTL与髓样来源的抑制细胞和调节性T细胞成反比。GBM微血管的转录组分析表明，三联疗法后全球血管正常化程度最高。我们的研究结果提出了通过整合VEGF / Ang-2和PD-1阻断剂的协同作用以通过标准化脉管系统增强抗肿瘤免疫力，从而克服肿瘤免疫抑制和VEGF单一疗法目前存在的局限性的基本原理。GBM微血管的转录组分析表明，三联疗法后全球血管正常化程度最高。我们的研究结果提出了通过整合VEGF / Ang-2和PD-1阻断剂的协同作用以通过标准化脉管系统增强抗肿瘤免疫力来克服肿瘤免疫抑制和VEGF单一疗法当前局限性的基本原理。GBM微血管的转录组分析表明，三联疗法后全球血管正常化程度最高。我们的研究结果提出了通过整合VEGF / Ang-2和PD-1阻断剂的协同作用以通过标准化脉管系统增强抗肿瘤免疫力，从而克服肿瘤免疫抑制和VEGF单一疗法目前存在的局限性的基本原理。