Immunosuppression in Glioblastoma: Current Understanding and Therapeutic Implications

Abstract

Glioblastoma (GBM) is the most common primary brain tumor in adults an carries and carries a terrible prognosis. The current regiment of surgical resection, radiation, and chemotherapy has remained largely unchanged in recent years as new therapeutic approaches have struggled to demonstrate benefit. One of the most challenging hurdles to overcome in developing novel treatments is the profound immune suppression found in many GBM patients. This limits the utility of all manner of immunotherapeutic agents, which have revolutionized the treatment of a number of cancers in recent years, but have failed to show similar benefit in GBM therapy. Understanding the mechanisms of tumor-mediated immune suppression in GBM is critical to the development of effective novel therapies, and reversal of this effect may prove key to effective immunotherapy for GBM. In this review, we discuss the current understanding of tumor-mediated immune suppression in GBM in both the local tumor microenvironment and systemically. We also discuss the effects of current GBM therapy on the immune system. We specifically explore some of the downstream effectors of tumor-driven immune suppression, particularly myeloid-derived suppressor cells (MDSCs) and other immunosuppressive monocytes, and the manner by which GBM induces their formation, with particular attention to the role of GBM-derived extracellular vesicles (EVs). Lastly, we briefly review the current state of immunotherapy for GBM and discuss additional hurdles to overcome identification and implementation of effective therapeutic strategies.

The Interplay of Tumor Vessels and Immune Cells Affects Immunotherapy of Glioblastoma

“…The aberrant vasculature, along with tumor cells, glioma-stem-like cells, resident (microglia), and peripheral myeloid cells via immunomodulatory factors such as: TGF-β, migration inhibitory factor (MIF), interleukin 6 and 10 (IL-6, IL-10), prostaglandin E-2 (PGE-2), and surface ligands: PD-LI, lead ultimately to T cell exhaustion and anergy. Infiltration of Tregs that blunt the antitumor T cell response, loss or reduced expression of major histocompatibility complex (MHC II) by antigen-presenting cells (APCs) such as microglia, M2-like GAMs, and infiltrating neutrophils expressing arginase-1, cooperate to induce severe immunosuppression [ 67 , 68 ]. CD95 (Fas/APO-1), a death receptor family member that regulates tissue homeostasis of the immune system by inducing apoptosis, has been implicated in tumorigenicity in multiple cancers, including GBM.…”

Advances in Nanotechnology-Based Immunotherapy for Glioblastoma

“…Therefore, developing strategies that can not only deliver the therapeutic agents efficiently across the BBB but also reverse the strong immunosuppressive microenvironment of GBM is of great significance for effective GBM immunotherapy. Most recent advances in understanding the physiology of the BBB, GBM microenvironment (GME), and the immunosuppressive mechanism of GBM have provided us with great opportunities to develop effective immunotherapeutics against GBM ( 12 – 14 ). The emergence of nanotechnologies provides a new development direction for the efficient targeted delivery of drugs to overcome physiological barriers and active targeting of specific cell populations, such as tumor cells/immune cell subsets.…”

Development of a Novel Prognostic Model of Glioblastoma Based on m6A-Associated Immune Genes and Identification of a New Biomarker

“…Although studies on immunotherapy against glioblastoma have included various approaches (immune checkpoint blockade, vaccine therapies, chimeric antigen receptor T-cell therapies, and oncolytic viral therapies), none have shown a definite effect in phase 3 trials ( 4 ). The main reason for this situation lies in the local and systemic immunosuppression observed in glioblastoma patients, and the mechanism underlying the latter remains largely unknown ( 14 ). Regarding local immunosuppression, we should first note that glioblastoma is a highly vascularized malignant tumor with dense tortuous and leaky blood vessels, allowing many immune cells to infiltrate the tumor core.…”

“…Cells infiltrating the tumor include microglia-derived and bone marrow-derived tumor-associated macrophages, microglia, and T cells ( 15 ). The immune microenvironment mainly mediates three immunosuppression aspects: changes in glioblastoma cell surface molecules inhibit the immune response ( 16 – 18 ); the glioblastoma microenvironment is rich in immunosuppression-mediating factors, including transforming growth factor β (TGF-β) ( 19 ), interleukin 10 (IL-10) ( 20 ), prostaglandin E-2 (PGE2) ( 21 ), colony-stimulating factor 1 (CSF-1) ( 22 ), vascular endothelial growth factor (VEGF) ( 23 ), arginase 1 ( 24 ), indoleamine 2,3-dioxygenase (IDO) ( 25 ), macrophage migration inhibitory factor (MIF) ( 26 ), and interleukin-6 (IL-6) ( 27 ); immunosuppressive cells such as regulatory T cells (Tregs) ( 28 ), tumor-associated macrophages ( 29 ), and monocytes with an immunosuppressive phenotype ( 14 ) are over-represented in the glioblastoma microenvironment. It is worth mentioning that the medium-level mutational burden of glioblastoma implies that the lack of a defining mutation hinders the development of targeted therapy and immunotherapy ( 30 ).…”