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

By Elizabeth Allen, A. Jabouille, Lee B. Rivera, I. Lodewijckx, R. Missiaen, V. Steri, Kevin Feyen, Jaime Tawney, D. Hanahan, I. Michael and 1 more. Science Translational Medicine, 2017

746 citations recorded by the source corpus.

Efficacy of antiangiogenic immunotherapy is associated with intratumoral formation of high endothelial venules. 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. 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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/a4dca1588990abf2598d251a4495a05eb50c6f34

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Citations in the corpus

VEGF in Signaling and Disease: Beyond Discovery and Development (2019, background): “Recent preclinical studies have also shown that antiVEGF therapy can improve anti-PD-L1 (programmed deathligand 1) treatment, specifically when it generates intratumoral high endothelial venules (HEVs) that facilitate enhanced cytotoxic T lymphocyte (CTL) infiltration and tumor cell destruction (All”
Tertiary lymphoid structures in cancer (2022, background): “In addition, evidence that TLSs can be therapeutically induced and associate with tumor control was obtained in mouse models of breast and neuroendocrine pancreatic cancers, in which the combination of PD-L1 blockade with antiangiogenic therapies resulted in the transformation of tumor blood vessels”
Targeting Tumor Microenvironment for Cancer Therapy (2019, background): “Following Allen and co-worker’s discovery [158], clinical trials have analyzed the use of combined therapies with agents targeting the immune system and angiogenesis.”
Functional morphology of the blood-brain barrier in health and disease (2018, background): “Studies following VEGF monotherapy or combined VEGF/Ang-2 targeting in preclinical GBM models demonstrated a more normalised vasculature [106, 110].”