EnLIGHTenment of tumor vessel normalization and immunotherapy in glioblastoma

Abstract

Glioblastoma multiforme (GBM) is a highly vascularized and aggressive brain tumor. Despite aggressive standard care, GBM remains predominantly fatal; hence, new innovative therapies are required. Recent research published in the Journal of Pathology has identified the CGKRK peptide as a promising tool with which to specifically target the tumor vasculature from high-grade glioma. This tumor vessel-homing peptide was fused to the tumor necrosis factor superfamily member LIGHT/TNFSF14, and injected intravenously into murine orthotopic GBM models. After treatment, the tumor vasculature appeared to be less abnormal, with normalized features such as increased endothelial barrier integrity, pericyte contractility, and tumor perfusion. Moreover, CGKRK-LIGHT induced the appearance of high endothelial venules (HEVs), which are specialized structures that play a role in lymphocyte trafficking and have been shown to increase T-cell infiltration in solid tumors. Combining CGKRK-LIGHT with anti-angiogenic and immune checkpoint blockade treatments boosted HEV induction and cytotoxic T-cell infiltration, leading to a reduction in tumor burden. In this Commentary, I highlight the therapeutic opportunities provided by and the current limitations of LIGHT-vascular targeting peptide as a new approach to target GBM and enhance tumor vessel delivery and immunotherapy efficacy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Tertiary Lymphoid Structures in Cancer: The Double-Edged Sword Role in Antitumor Immunity and Potential Therapeutic Induction Strategies

“…Macrophages and T cells have been deemed essential for HEV and TLS formation ( 83 , 113 ) ( Figure 3A ). LIGHT-VTP in combination with ICB therapy can produce intratumoral memory T cells and Teff cells and improve prognosis ( 114 ). In addition, LIGHT-VTP combined with anti-VEGF and ICB therapy can increase the frequency of HEVs and normalize tumor vessels and the accumulation of T cells in glioblastoma and lung metastases ( 115 , 116 ).…”

High endothelial venules as potential gateways for therapeutics

“…HEVs can be differentiated from other blood vessels by their expression of PNAd glycoproteins, recognized by a group of antibodies. These antibodies have resulted in the identification of ectopically formed HEVs in organs affected by inflammatory conditions, autoimmune diseases, or cancers [10,[14][15][16][17][18][19][20][21][22][36][37][38][39][40][41]55,64,74].…”

Tumor Vessel Normalization: A Window to Enhancing Cancer Immunotherapy

“…Additionally, high endothelial venules (HEVs) appeared, and T cell infiltration also increased. 109 Increasing studies have shown that immune cells also play roles in tumor vessel normalization. Thus, stimulation of such immune cells may be a new strategy to normalize the tumor vasculature.…”