Research ArticleCancer

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

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Science Translational Medicine  12 Apr 2017:
Vol. 9, Issue 385, eaak9679
DOI: 10.1126/scitranslmed.aak9679

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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

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.

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