Hamon Center for Therapeutic Oncology Research.
Department of Surgery.
JCI Insight. 2021 Dec 8;6(23):e150735. doi: 10.1172/jci.insight.150735.
Angiogenesis, a hallmark of cancer, is induced by vascular endothelial growth factor-A (hereafter VEGF). As a result, anti-VEGF therapy is commonly used for cancer treatment. Recent studies have found that VEGF expression is also associated with immune suppression in patients with cancer. This connection has been investigated in preclinical and clinical studies by evaluating the therapeutic effect of combining antiangiogenic reagents with immune therapy. However, the mechanisms of how anti-VEGF strategies enhance immune therapy are not fully understood. We and others have shown selective elevation of VEGFR2 expression on tumor-associated myeloid cells in tumor-bearing animals. Here, we investigated the function of VEGFR2+ myeloid cells in regulating tumor immunity and found VEGF induced an immunosuppressive phenotype in VEGFR2+ myeloid cells, including directly upregulating the expression of programmed cell death 1 ligand 1. Moreover, we found that VEGF blockade inhibited the immunosuppressive phenotype of VEGFR2+ myeloid cells, increased T cell activation, and enhanced the efficacy of immune checkpoint blockade. This study highlights the function of VEGFR2 on myeloid cells and provides mechanistic insight on how VEGF inhibition potentiates immune checkpoint blockade.
血管生成是癌症的一个标志，它是由血管内皮生长因子 A（以下简称 VEGF）诱导的。因此，抗 VEGF 治疗通常用于癌症治疗。最近的研究发现，VEGF 的表达也与癌症患者的免疫抑制有关。通过评估联合抗血管生成试剂与免疫治疗的治疗效果，已经在临床前和临床研究中研究了这种联系。然而，抗 VEGF 策略如何增强免疫治疗的机制尚不完全清楚。我们和其他人已经表明，在荷瘤动物中，肿瘤相关髓样细胞上 VEGFR2 的表达选择性升高。在这里，我们研究了 VEGFR2+髓样细胞在调节肿瘤免疫中的作用，发现 VEGF 诱导了 VEGFR2+髓样细胞的免疫抑制表型，包括直接上调程序性细胞死亡配体 1 的表达。此外，我们发现 VEGF 阻断抑制了 VEGFR2+髓样细胞的免疫抑制表型，增加了 T 细胞的激活，并增强了免疫检查点阻断的疗效。这项研究强调了 VEGFR2 在髓样细胞上的功能，并提供了关于 VEGF 抑制如何增强免疫检查点阻断的机制见解。
