Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules

Abstract

High-grade brain cancer such as glioblastoma (GBM) remains an incurable disease. A common feature of GBM is the angiogenic vasculature, which can be targeted with selected peptides for payload delivery. We assessed the ability of micelle-tagged, vascular homing peptides RGR, CGKRK and NGR to specifically bind to blood vessels in syngeneic orthotopic GBM models. By using the peptide CGKRK to deliver the tumour necrosis factor (TNF) superfamily member LIGHT (also known as TNF superfamily member 14; TNFSF14) to angiogenic tumour vessels, we have generated a reagent that normalizes the brain cancer vasculature by inducing pericyte contractility and re-establishing endothelial barrier integrity. LIGHT-mediated vascular remodelling also activates endothelia and induces intratumoural high endothelial venules (HEVs), which are specialized blood vessels for lymphocyte infiltration. Combining CGKRK-LIGHT with anti-vascular endothelial growth factor and checkpoint blockade amplified HEV frequency and T-cell accumulation in GBM, which is often sparsely infiltrated by immune effector cells, and reduced tumour burden. Furthermore, CGKRK and RGR peptides strongly bound to blood vessels in freshly resected human GBM, demonstrating shared peptide-binding activities in mouse and human primary brain tumour vessels. Thus, peptide-mediated LIGHT targeting is a highly translatable approach in primary brain cancer to reduce vascular leakiness and enhance immunotherapy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Remodeling of Metastatic Vasculature Reduces Lung Colonization and Sensitizes Overt Metastases to Immunotherapy

“…Although this does not impact on primary tumor growth, it reduces the release of cancer cells into the circulation. LIGHT-mediated vessel normalization is predominantly effected through pericyte maturation but also upregulates endothelial adherens junctions (He et al, 2018;Johansson-Percival et al, 2015). Our findings are consistent with other studies, which have shown that improving endothelial cell barrier function, for instance by genetic targeting of VE-cadherin, tie2/angiopoietin2 (Ang2), or tie1, increases tumor perfusion and oxygenation, leading to reduced metastatic tumor dissemination (Cantelmo et al, 2016;La Porta et al, 2018;Mazzone et al, 2009;Park et al, 2016).…”

“…In highly angiogenic primary mouse tumors, such as insulinoma and glioblastoma, LIGHT-VTP reverses vessel abnormalities and induces intratumoral high endothelial venules (HEVs); this specialized vessel structure greatly facilitates leukocyte migration and de novo formation of intratumoral lymph node structures, which resemble TLSs (He et al, 2018;Johansson-Percival et al, 2015.…”

A LIGHTning Strike to the Metastatic Niche

“…HEVs are endowed with cuboidal-rather than flat-endothelial cells that facilitate extravasation of circulating lymphocytes, in part by secreting the T cell chemoattractant CCL21. Accordingly, LIGHT-mediated induction of intra-tumoral HEVs was associated with higher T cell numbers and a better tumor response to immune checkpoint blockade (He et al, 2018).…”

“…It binds both lymphotoxin-beta receptor (LTBR), which is expressed on various tumorassociated stromal cells, and Herpesvirus-entry mediator (HVEM), which is expressed on lymphoid cells (Tamada et al, 2000). Previous work has shown that a LIGHT variant engineered to target the angiogenic vasculature through an angiotropic peptide (LIGHT-VTP) could reprogram the blood vessels in experimental brain tumors (He et al, 2018). Notably, LIGHT-VTP converted a fraction of the tumor blood vessels into high endothelial venules (HEVs), which are specialized vessels present in most lymphoid tissues.…”

“…First, it impairs the escape of cancer cells from the primary tumor, a process that is partly dependent on their ability to invade tumor blood vessels (intravasation). LIGHT-VTP may limit cancer-cell intravasation by increasing endothelial barrier integrity in the primary tumor (He et al, 2018), as seen with other vascularnormalizing agents, such as angiopoietin-2 blocking antibodies (Holopainen et al, 2012;Schmittnaegel et al, 2017). Second, LIGHT-VTP limits the arrival of cancer cells to the lung, likely by making the pulmonary vasculature less permissive to their extravasation.…”