Departments of Molecular, Cell and Cancer Biology, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA.
Program in Molecular Medicine, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA.
Sci Transl Med. 2023 May 3;15(694):eade5855. doi: 10.1126/scitranslmed.ade5855.
Prostate cancers are largely unresponsive to immune checkpoint inhibitors (ICIs), and there is strong evidence that programmed death-ligand 1 (PD-L1) expression itself must be inhibited to activate antitumor immunity. Here, we report that neuropilin-2 (NRP2), which functions as a vascular endothelial growth factor (VEGF) receptor on tumor cells, is an attractive target to activate antitumor immunity in prostate cancer because VEGF-NRP2 signaling sustains PD-L1 expression. depletion increased T cell activation in vitro. In a syngeneic model of prostate cancer that is resistant to ICI, inhibition of the binding of VEGF to NRP2 using a mouse-specific anti-NRP2 monoclonal antibody (mAb) resulted in necrosis and tumor regression compared with both an anti-PD-L1 mAb and control immunoglobulin G. This therapy also decreased tumor PD-L1 expression and increased immune cell infiltration. We observed that the , , and genes are amplified in metastatic castration-resistant and neuroendocrine prostate cancer. We also found that individuals with NRP2 PD-L1 metastatic tumors had lower androgen receptor expression and higher neuroendocrine prostate cancer scores than other individuals with prostate cancer. In organoids derived from patients with neuroendocrine prostate cancer, therapeutic inhibition of VEGF binding to NRP2 using a high-affinity humanized mAb suitable for clinical use also diminished PD-L1 expression and caused a substantial increase in immune-mediated tumor cell killing, consistent with the animal studies. These findings provide justification for the initiation of clinical trials using this function-blocking NRP2 mAb in prostate cancer, especially for patients with aggressive disease.
前列腺癌对免疫检查点抑制剂（ICIs）反应不佳，有强有力的证据表明，程序性死亡配体 1（PD-L1）表达本身必须被抑制才能激活抗肿瘤免疫。在这里，我们报告神经纤毛蛋白-2（NRP2），作为肿瘤细胞上的血管内皮生长因子（VEGF）受体，是激活前列腺癌抗肿瘤免疫的一个有吸引力的靶点，因为 VEGF-NRP2 信号维持 PD-L1 表达。NRP2 耗竭增加了体外 T 细胞的激活。在对 ICI 耐药的前列腺癌同基因模型中，使用针对 NRP2 的小鼠特异性抗 NRP2 单克隆抗体（mAb）抑制 VEGF 与 NRP2 的结合，与抗 PD-L1 mAb 和对照免疫球蛋白 G 相比，导致坏死和肿瘤消退。这种治疗方法还降低了肿瘤 PD-L1 表达并增加了免疫细胞浸润。我们观察到，在转移性去势抵抗和神经内分泌前列腺癌中扩增了 、 和 基因。我们还发现，与其他前列腺癌患者相比，NRP2 PD-L1 转移性肿瘤患者的雄激素受体表达较低，神经内分泌前列腺癌评分较高。在源自神经内分泌前列腺癌患者的类器官中，使用适合临床使用的高亲和力人源化 mAb 抑制 VEGF 与 NRP2 的结合也减少了 PD-L1 表达，并导致免疫介导的肿瘤细胞杀伤显著增加，与动物研究一致。这些发现为在前列腺癌中使用这种功能阻断 NRP2 mAb 启动临床试验提供了依据，特别是对侵袭性疾病患者。
