Immune Checkpoint Inhibitors in Human Glioma Microenvironment

Abstract

Gliomas are the most common primary brain tumors in adults. Despite the fact that they are relatively rare, they cause significant morbidity and mortality. High-grade gliomas or glioblastomas are rapidly progressing tumors with a very poor prognosis. The presence of an intrinsic immune system in the central nervous system is now more accepted. During the last decade, there has been no major progress in glioma therapy. The lack of effective treatment for gliomas can be explained by the strategies that cancer cells use to escape the immune system. This being said, immunotherapy, which involves blockade of immune checkpoint inhibitors, has improved patients' survival in different cancer types. This novel cancer therapy appears to be one of the most promising approaches. In the present study, we will start with a review of the general concept of immune response within the brain and glioma microenvironment. Then, we will try to decipher the role of various immune checkpoint inhibitors within the glioma microenvironment. Finally, we will discuss some promising therapeutic pathways, including immune checkpoint blockade and the body's effective anti-glioma immune response.

Keywords: Glioblastoma; Glioma; immune checkpoint; immune response; immunotherapy.

Figure 1

Immunosuppressive microenvironment of glioma. Tumor cells release molecules which contribute to multiple unique immunosuppression mediated by various cellular players in glioma microenvironment. (A) After recruitment to the tumor site, Tregs directly suppress the activity of cytolytic T cells and induce their apoptosis through secretion of various types of cytokines including IL-10 and TGFβ. (B) Angiogenesis is a pathologic hallmark of glioblastoma mainly mediated by vascular endothelial growth factor (VEGF). (C) Immune checkpoints suppress T cell function in glioma microenvironment through distinct mechanisms.

Figure 2

Immune checkpoint blockade in gliomas. The mechanisms by which various immune checkpoints promote each other and contribute to the immunosuppressive microenvironment in gliomas. PD-1/PD-L1, CTLA-4/B7, TIM3/GAL9, and TIGIT/CD96 expressed on different types of immune cells such as T cells (CD4 and CD8) Dendritic cells (DC), Natural killer cells (NK) B cells. These pathways could induce FoxP3 expression and promote tumor escape, cytotoxic cell inhibition and Treg conversion with the help of TGF-β and IL-10. The blockade of these immune checkpoint molecules through mono or combined therapy could be used as a potential therapeutic for glioma and especially glioblastoma.

Figure 3

Immune checkpoint inhibitors in glioblastoma. The CTLA-4 immune checkpoint (A) operates early during the priming phase of the immune response. CTLA-4 preferentially binds to CD80/CD86 on the surface of APCs, thus leading to decreased T-cell activation and proliferation in the context of tumor antigen presentation. The T cell-expressed inhibitory PD-1 receptor interacts with PD-L1 (B), which is expressed on tumor cells. Engagement of PD-1 and PDL-1, in the context of tumor antigen- presentation by MHC class I molecules, induces T cell apoptosis, inhibits T cell activation/cytotoxicity, promotes Tregs proliferation and blocks the production of inflammatory mediators, resulting in T cell inactivity. TIM-3/GAL-9 pathway (C) negatively regulates T cell immunity and induces T cell apoptosis. *ICP, Immune Checkpoint.