Glioblastoma Immune Landscape and the Potential of New Immunotherapies

Abstract

Glioblastoma (GBM) are the most common tumors of the central nervous system and among the deadliest cancers in adults. GBM overall survival has not improved over the last decade despite optimization of therapeutic standard-of-care. While immune checkpoint inhibitors (ICI) have revolutionized cancer care, they unfortunately have little therapeutic success in GBM. Here, we elaborate on normal brain and GBM-associated immune landscapes. We describe the role of microglia and tumor-associated macrophages (TAMs) in immune suppression and highlight the impact of energy metabolism in immune evasion. We also describe the challenges and opportunities of immunotherapies in GBM and discuss new avenues based on harnessing the anti-tumor activity of myeloid cells, vaccines, chimeric antigen receptors (CAR)-T and -NK cells, oncolytic viruses, nanocarriers, and combination therapies.

Keywords: CART-T cell; glioblastoma; immune response; immunotherapy; macrophage.

Figure 1

Architecture of the CNS immune system. (A) Schematic illustration of the human brain anatomy namely the brain parenchyma, choroid plexus, ventricles, cerebrospinal fluid (CSF), meninges, dural and nasal lymphatics and the deep cervical lymph nodes (DCLNs). (B) The meninges. These are three membranes that envelop the brain, namely the dura mater, the arachnoid membrane and the pia mater. (C) The neurovascular unit (NVU), blood brain barrier (BBB) and perivascular space. The glia limitans formed by astrocytes end feet ensheath the capillary basement membrane and its pericytes. The perivascular space contains microglia-like perivascular macrophages also dubbed border-associated macrophages (BAMs) and antigen-presenting cells (APC). Microglia are found in the brain parenchyma. (D) The glymphatic system. The CSF enters the brain parenchyma through aquaporin 4, water channels on the end-feet of astrocytes surrounding the vasculature, and communicates with the interstitial fluid (ISF) carrying solutes and small antigens through the glymphatic system, a network of perivascular channels formed by astroglia for waste elimination.

Figure 2

Molecular classification of gliomas. Adapted from the 2016 WHO classification of brain tumors by DeWitt JC et al. (26).

Figure 3

TAM ontogeny and tumor geography in GBM. Tumor-associated macrophages (TAMs) in GBM originates from microglia (MG-TAMs) or from bone marrow-derived monocytes differentiating into macrophages upon recruitment (BM-TAMs). These can be distinguished based on the differential expression of the integrin CD49D on BM-TAMs and of the purinergic receptor P2RY12 on MG-TAMs. BM-TAMs that infiltrate into the tumor core are smaller and less branched than MG-TAMs that are found in the peri-tumoral area.

Figure 4

Immunotherapies for the treatment of GBM. Classical immune checkpoint inhibitors (ICI) i.e., anti-PD-1/PDL-1 and anti-CTLA4 were ineffective in GBM. Current approaches include modulating TAMs (anti-CD47 to boost phagocytosis, nano-immunoconjugates to modulate TAM phenotype, aptamers to inhibit TAM recruitment), personalized peptide vaccines, chimeric antigen receptor (CAR)-T and CAR-NK cell approaches and oncolytic viruses. BiTEs, Bi-specific T-cell engagers.