Recent Advances in Glioma Therapy: Combining Vascular Normalization and Immune Checkpoint Blockade

Abstract

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.

Keywords: angiogenesis; glioblastoma; immune checkpoint blockade; immune microenvironment.

Figure 1

Schematic representation of glioma angiogenesis. As tumor growth within the brain parenchyma goes beyond 1–2 mm in diameter, its metabolic demands cannot be met entirely via diffusion. (1) Hypoxia then occurs to regulate angiogenic signals. (2) The activation of autocrine and paracrine ANGPT2/TIE2 signaling subsequently disrupts endothelial–mural cell interactions for vessel regression. (3,4) HIF-1α upregulation induces the transcriptional activation of proangiogenic molecules that initiate EC proliferation and migration. (5) Simultaneously, increased ANGPT2 activates MMP-2 to degrade the ECM. (6) Proteolysis of the vessel’s basement membrane facilitates the migration and proliferation of ECs toward the hypoxic tumor core. Lastly, the blood vessel wall matures, as (7) pericytes are recruited along the ECs to stabilize the blood vessel. (8) Endogenous protease inhibitors and antiangiogenic factors locally halt ECM proteolysis to hinder further vessel remodeling.

Figure 2

Crosstalk between immune cells and angiogenesis in glioblastoma. Glioma angiogenesis is the result of complex interactions with the immunosuppressive TME that consists of glioma cells, GSCs, and the various immune cells. M1-like and M2-like macrophages are polarized via T_H1-derived IFN-γ and T_H2-derived IL-4/IL-13, respectively, to mediate angiogenesis. The expansion of Treg releases VEGF-A to sustain tumor vessel growth. B cells modulate angiogenesis directly by producing STAT-3-dependent VEGF-A and MMP-9. VEGF signaling hinders DC maturation and its antigen presentation, suppresses effector T-cell functions via inhibitory immune checkpoint stimulation, and enhances MDSCs immunosuppressive activity, leading to glioma immune evasion. Macrophage migration inhibitory factor (MIF) secreted by GSCs and glioma cells acts on MDSCs-driven T-cell dysfunction. An M2-like TAMs phenotype can be further promoted by GSC-derived WISP-1 via the integrin α6β1/pAKT axis. Crosstalk between glioma cells and M2-like TAMs via various chemokines and cytokines occurs to enhance immune suppression and angiogenesis, as well as tumor cell proliferation.