Research ArticleCancer

Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade

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Science Translational Medicine  12 Apr 2017:
Vol. 9, Issue 385, eaak9670
DOI: 10.1126/scitranslmed.aak9670

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Antitumor attack on two fronts

The use of immune checkpoint inhibitors and other immunotherapies for the treatment of cancer is continuing to expand as these drugs demonstrate effectiveness in progressively more cancer types and therapeutic contexts. At the same time, the drugs are not perfect, and not all patients respond to them, so a key subject of research in this field is determining optimal ways to combine immune checkpoint therapies with other cancer treatments. Schmittnaegel et al. and Allen et al. focused their studies on the combination of antiangiogenic treatments with checkpoint inhibitors. The authors demonstrated how inhibition of tumor angiogenesis can facilitate the access of cytotoxic T cells to tumors, while the checkpoint inhibitors protect these T cells from exhaustion, enhancing their antitumor effects.

Abstract

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.

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