title: Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation.
abstract: Inhibitors of VEGF (vascular endothelial growth factor)/VEGFR2 (vascular endothelial growth factor receptor 2) are commonly used in the clinic, but their beneficial effects are only observed in a subset of patients and limited by induction of diverse relapse mechanisms. We describe the up-regulation of an adaptive immunosuppressive pathway during antiangiogenic therapy, by which PD-L1 (programmed cell death ligand 1), the ligand of the negative immune checkpoint regulator PD-1 (programmed cell death protein 1), is enhanced by interferon-γ-expressing T cells in distinct intratumoral cell types in refractory pancreatic, breast, and brain tumor mouse models. Successful treatment with a combination of anti-VEGFR2 and anti-PD-L1 antibodies induced high endothelial venules (HEVs) in PyMT (polyoma middle T oncoprotein) breast cancer and RT2-PNET (Rip1-Tag2 pancreatic neuroendocrine tumors), but not in glioblastoma (GBM). These HEVs promoted lymphocyte infiltration and activity through activation of lymphotoxin β receptor (LTβR) signaling. Further activation of LTβR signaling in tumor vessels using an agonistic antibody enhanced HEV formation, immunity, and subsequent apoptosis and necrosis in pancreatic and mammary tumors. Finally, LTβR agonists induced HEVs in recalcitrant GBM, enhanced cytotoxic T cell (CTL) activity, and thereby sensitized tumors to antiangiogenic/anti-PD-L1 therapy. Together, our preclinical studies provide evidence that anti-PD-L1 therapy can sensitize tumors to antiangiogenic therapy and prolong its efficacy, and conversely, antiangiogenic therapy can improve anti-PD-L1 treatment specifically when it generates intratumoral HEVs that facilitate enhanced CTL infiltration, activity, and tumor cell destruction.
authors.affiliation: Laboratory of Tumor Microenvironment and Therapeutic Resistance, VIB-Center for Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Elizabeth
authors.identifier: 0000-0002-5379-2668
authors.initials: E
authors.lastname: Allen
authors.affiliation: Brain Tumor Research Center, Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Arnaud
authors.identifier: 0000-0002-2281-430X
authors.initials: A
authors.lastname: Jabouille
authors.affiliation: Brain Tumor Research Center, Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Lee B
authors.identifier: 0000-0003-2658-1862
authors.initials: LB
authors.lastname: Rivera
authors.affiliation: Laboratory of Tumor Microenvironment and Therapeutic Resistance, VIB-Center for Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Lodewijckx
authors.affiliation: Laboratory of Tumor Microenvironment and Therapeutic Resistance, VIB-Center for Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Rindert
authors.identifier: 0000-0002-8192-0567
authors.initials: R
authors.lastname: Missiaen
authors.affiliation: Brain Tumor Research Center, Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Steri
authors.affiliation: Laboratory of Tumor Microenvironment and Therapeutic Resistance, VIB-Center for Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Kevin
authors.initials: K
authors.lastname: Feyen
authors.affiliation: Brain Tumor Research Center, Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Tawney
authors.affiliation: Swiss Institute for Experimental Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Station 19, 1015 Lausanne, Switzerland.
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
authors.affiliation: Swiss Institute for Experimental Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Station 19, 1015 Lausanne, Switzerland.
authors.forename: Iacovos P
authors.identifier: 0000-0001-7674-1233
authors.initials: IP
authors.lastname: Michael
authors.affiliation: Laboratory of Tumor Microenvironment and Therapeutic Resistance, VIB-Center for Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium. gabriele.bergers@kuleuven.vib.be.|Brain Tumor Research Center, Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Gabriele
authors.identifier: 0000-0003-3545-5171
authors.initials: G
authors.lastname: Bergers
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000628:therapy; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009364:Neoplasm Recurrence, Local; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000628:therapy; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D020533:Angiogenesis Inhibitors; D061026:Programmed Cell Death 1 Receptor; D042461:Vascular Endothelial Growth Factor A; D007371:Interferon-gamma