Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade
Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade
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DOI：
10.1126/scitranslmed.aak9670
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发表时间：
2017-04-12
影响因子：
17.1
通讯作者：
De Palma, Michele
中科院分区：
文献类型：
--
作者：
Schmittnaegel, Martina;Rigamonti, Nicolo;De Palma, Michele
病理性血管生成是癌症的标志和治疗靶点。血管内皮生长因子A（VEGFA）和血管生成素-2（ANGPT 2;也称为ANG 2）是维持肿瘤血管生成并限制抗肿瘤免疫的促血管生成细胞因子。我们表明，在基因工程和移植肿瘤模型中，包括转移性乳腺癌（MMTV-PyMT）、胰腺神经内分泌肿瘤（RIP 1-Tag 2）和黑色素瘤，与单一药物相比，双特异性抗体（A2 V）联合ANGPT 2和VEGFA阻断提供了上级治疗益处。从机制上讲，A2 V促进血管消退、肿瘤坏死和肿瘤内吞噬细胞的抗原呈递。A2 V还使剩余的血管正常化，并促进激活的表达干扰素-γ（IFN-γ）的CD 8（+）细胞毒性T淋巴细胞（CTL）的外渗和血管周围积聚。尽管A2 V的抗肿瘤活性至少部分是CTL依赖性的，但血管周围T细胞同时上调肿瘤内皮细胞中免疫检查点配体程序性细胞死亡配体1（PD-L1）的表达。IFNg中和减弱了这种适应性反应，PD-1阻断改善了A2 V在不同癌症模型中的肿瘤控制。这些发现将免疫细胞定位为抗血管生成治疗的关键效应物，并支持在癌症治疗中共同靶向血管生成和免疫检查点的基本原理。
Pathological angiogenesis is a hallmark of cancer and a therapeutic target. Vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2; also known as ANG2) are proangiogenic cytokines that sustain tumor angiogenesis and limit antitumor immunity. We show that combined ANGPT2 and VEGFA blockade by a bispecific antibody (A2V) provided superior therapeutic benefits, as compared to the single agents, in both genetically engineered and transplant tumor models, including metastatic breast cancer (MMTV-PyMT), pancreatic neuroendocrine tumor (RIP1-Tag2), and melanoma. Mechanistically, A2V promoted vascular regression, tumor necrosis, and antigen presentation by intratumoral phagocytes. A2V also normalized the remaining blood vessels and facilitated the extravasation and perivascular accumulation of activated, interferon-gamma (IFN gamma)-expressing CD8(+) cytotoxic T lymphocytes (CTLs). Whereas the antitumoral activity of A2V was, at least partly, CTL-dependent, perivascular T cells concurrently up-regulated the expression of the immune checkpoint ligand programmed cell death ligand 1 (PD-L1) in tumor endothelial cells. IFNg neutralization blunted this adaptive response, and PD-1 blockade improved tumor control by A2V in different cancer models. These findings position immune cells as key effectors of antiangiogenic therapy and support the rationale for cotargeting angiogenesis and immune checkpoints in cancer therapy.