title: Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade.
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.
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Martina
authors.identifier: 0000-0002-8037-5309
authors.initials: M
authors.lastname: Schmittnaegel
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Nicolò
authors.identifier: 0000-0002-5833-6995
authors.initials: N
authors.lastname: Rigamonti
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Ece
authors.initials: E
authors.lastname: Kadioglu
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Antonino
authors.initials: A
authors.lastname: Cassará
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Wyser Rmili
authors.affiliation: Roche Innovation Center Basel, Pharmaceutical Sciences, Pharma Research and Early Development, 4070 Basel, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kiialainen
authors.affiliation: Roche Innovation Center Munich, Oncology Discovery, Pharma Research and Early Development, 82377 Penzberg, Germany.
authors.forename: Yvonne
authors.identifier: 0000-0002-6623-5836
authors.initials: Y
authors.lastname: Kienast
authors.affiliation: Roche Innovation Center Munich, Oncology Discovery, Pharma Research and Early Development, 82377 Penzberg, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Mueller
authors.affiliation: Roche Innovation Center Basel, Pharmaceutical Sciences, Pharma Research and Early Development, 4070 Basel, Switzerland.|Roche Innovation Center Munich, Oncology Discovery, Pharma Research and Early Development, 82377 Penzberg, Germany.
authors.forename: Chia-Huey
authors.initials: CH
authors.lastname: Ooi
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Damya
authors.identifier: 0000-0002-3373-1403
authors.initials: D
authors.lastname: Laoui
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. michele.depalma@epfl.ch.
authors.forename: Michele
authors.identifier: 0000-0001-9128-5459
authors.initials: M
authors.lastname: De Palma
mesh_terms: D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D042702:Angiopoietin-2; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D042461:Vascular Endothelial Growth Factor A