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Sci Transl Med. 2017 Apr 12;9(385). pii: eaak9679. doi: 10.1126/scitranslmed.aak9679.

Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation.

Author information

1
Laboratory of Tumor Microenvironment and Therapeutic Resistance, VIB-Center for Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
2
Brain Tumor Research Center, Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Swiss Institute for Experimental Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Station 19, 1015 Lausanne, Switzerland.
4
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.

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.

PMID:
28404866
PMCID:
PMC5554432
DOI:
10.1126/scitranslmed.aak9679
[Indexed for MEDLINE]
Free PMC Article

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