Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Roche Innovation Center Basel, Pharmaceutical Sciences, Pharma Research and Early Development, 4070 Basel, Switzerland.
Sci Transl Med. 2017 Apr 12;9(385). doi: 10.1126/scitranslmed.aak9670.
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-γ (IFNγ)-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. IFNγ 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.
病理性血管生成是癌症的一个标志，也是一个治疗靶点。血管内皮生长因子 A（VEGFA）和血管生成素-2（ANGPT2；也称为 ANG2）是促血管生成细胞因子，它们维持肿瘤血管生成并限制抗肿瘤免疫。我们发现，与单一药物相比，双特异性抗体（A2V）同时阻断 ANGPT2 和 VEGFA 可在基因工程和移植肿瘤模型中提供更好的治疗效果，包括转移性乳腺癌（MMTV-PyMT）、胰腺神经内分泌肿瘤（RIP1-Tag2）和黑色素瘤。从机制上讲，A2V 促进血管退化、肿瘤坏死和肿瘤内吞噬细胞的抗原呈递。A2V 还使剩余的血管正常化，并促进激活的、表达干扰素-γ（IFNγ）的 CD8 细胞毒性 T 淋巴细胞（CTL）的血管外渗和血管周围积聚。尽管 A2V 的抗肿瘤活性至少部分依赖于 CTL，但血管周围 T 细胞同时上调了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。IFNγ 中和削弱了这种适应性反应，而 PD-1 阻断在不同的癌症模型中改善了 A2V 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同时靶向血管生成和免疫检查点的原理。
