Abstract
Simple SummaryGlioblastoma is the most malignant tumor of the brain. Over the years, prognosis for patients with glioblastoma has remained dismal despite advances in medical sciences. Glioblastoma is a highly vascularized tumor; however, antiangiogenic therapy has not achieved the expected outcome. Recent promising results from immunotherapies for other cancer types such as melanoma have prompted the further investigation of combining antiangiogenic therapy with immune checkpoint blockade. This article aims to provide an overview concerning the development of a potential intervention that may enhance the efficacy of immune checkpoint blockade as glioblastoma therapy.Glioblastoma (GBM) accounts for more than 50% of all primary malignancies of the brain. Current standard treatment regimen for GBM includes maximal surgical resection followed by radiation and adjuvant chemotherapy. However, due to the heterogeneity of the tumor cells, tumor recurrence is often inevitable. The prognosis of patients with glioma is, thus, dismal. Glioma is a highly angiogenic tumor yet immunologically cold. As such, evolving studies have focused on designing strategies that specifically target the tyrosine kinase receptors of angiokines and encourage immune infiltration. Recent promising results from immunotherapies on other cancer types have prompted further investigations of this therapy in GBM. In this article, we reviewed the pathological angiogenesis and immune reactivity in glioma, as well as its target for drug development, and we discussed future directions in glioma therapy.
Highlights
Glioblastoma (GBM), WHO grade IV tumor, is the most common and aggressive primary brain tumor in adult with a dismal prognosis of not more than 15 months
The differential localization of these two populations of tumor-associated microglia/macrophages (TAMs) coincides with the expression of anti-inflammatory and proangiogenic factors such as IL-1 receptor antagonist (IL1-RN) [76] and vascular endothelial growth factor (VEGF) at the tumor core, suggesting that these cells crosstalk with endothelial cells (ECs) and glioma stem cells (GSCs) within the perivascular niche (PVN) to further support and amplify the expansion of tumor vasculature with irregular morphology and extracellular matrix (ECM) remodeling [75]
Immunity interaction, under which antiangiogenic treatment and immune checkpoint inhibitors need to target in order to exert their combined effects on glioma tumor microenvironment (TME)
Summary
Glioblastoma (GBM), WHO grade IV tumor, is the most common and aggressive primary brain tumor in adult with a dismal prognosis of not more than 15 months. Current standard of care for GBM includes maximal surgical resection followed by radiotherapy (RT), concurrent adjuvant chemotherapy using temozolomide (TMZ), and occasionally alternating electric field therapy (TTFields) [1,2] Despite these treatments, most tumors eventually develop resistance, resulting in recurrences of more aggressive tumors at the surgical sites or regions within 2–3 cm of the original tumor areas [3,4]. Signaling regulators essential for modulating angiogenesis, such as vascular endothelial growth factor (VEGF), platelet derived-growth factor (PDGF), angiopoietin (ANGPT), and transforming growth factor-β (TGF-β), as well as the angiogenic process, have been extensively reviewed [14,15] Such growth factors, cytokines, and chemokines secreted by glioma cells promote infiltration of cells including glioma stem cells (GSCs), endothelial cells (ECs), pericytes, reactive astrocytes, granulocytes, and immune cells, microglia, macrophages, myeloidderived suppressor cells (MDSCs), regulatory T (Treg ) cells, and effector T cells [8,16]. We appraise the combination of emerging viable strategies of antivascular and/or glioma immune microenvironment ICB interventions
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