Challenges in glioblastoma immunotherapy: mechanisms of resistance and therapeutic approaches to overcome them

Abstract

Glioblastoma is the most common and aggressive primary malignant brain tumour. The prognosis of patients with glioblastoma is poor, and their overall survival averages at 1 year, despite advances made in cancer therapy. The emergence of immunotherapy, a strategy that targets the natural mechanisms of immune evasion by cancerous cells, has revolutionised the treatment of melanoma, lung cancer and other solid tumours; however, immunotherapy failed to improve the prognosis of patients with glioblastoma. This is attributed to the fact that glioblastoma is endowed with numerous mechanisms of resistance that include the intrinsic resistance, which refers to the location of the tumour within the brain and the nature of the blood-brain barrier, as well as the adaptive and acquired resistance that result from the tumour heterogeneity and its immunosuppressive microenvironment. Glioblastoma is notorious for its inter and intratumoral heterogeneity, which, coupled with its spatial and temporal evolution, limits its immunogenicity. In addition, the tumour microenvironment is enriched with immunosuppressive cells and molecules that hinder the reactivity of cytotoxic immune cells and the success of immunotherapies. In this article, we review the mechanisms of resistance of glioblastoma to immunotherapy and discuss treatment strategies to overcome them worthy of further exploration.

Fig. 1. Schematic representation of the molecules that favour the immunosuppressive tumour microenvironment in glioblastoma, and the immunotherapeutic drugs that have been investigated in clinical trials to enhance the anti-tumour response.

Under hypoxic conditions, glioblastoma cells activate the hypoxia-inducible factor-1 (HIF-1) pathway, which stimulates angiogenesis through the expression of the vascular endothelial growth factor (VEGF). To tone down the immune system, glioblastoma cells upregulate immune checkpoint molecules such as PD-L1 and CTLA-4, inhibiting cytotoxic T cells. Similarly, through the action of indoleamine 2,3-dioxygenase-1 (IDO-1), the tumour metabolises tryptophan into kynurenine, which is released into the tumour microenvironment. Kynurenine diffuses into macrophages where it acts as a ligand to the aryl-hydrocarbon receptor (AHR), upregulating the expression of the transcription factor Krüppel-like factor 4 (KFL4) and favouring an M2 phenotype. The activation of the AHR also stimulates the expression of the suppressor of cytokine signalling 2 (SOCS2) and increases the degradation of tumour necrosis factor-associated factor 6 (TRAF6), limiting the activity of NF-κB. Macrophages also upregulate the expression of the ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD-1/CD39), which mediates the cleavage of ATP into adenosine. Adenosine acts through adenosine 2A receptors (A2AR) to activate regulatory T (Treg) cells and inhibit cytotoxic T cells. Both macrophages and Treg cells secrete inhibitory cytokines such as TGF-β and IL-10, further suppressing CD8⁺ T cells. In the inhibitory microenvironment, CD8⁺ T cells downregulate the expression of stimulatory cytokines such as IL-2, IFN-γ, TNF-α, and that of the activator protein 1 (AP-1) transcription factor. In contrast, Eomesodermins (Eomes) upregulate the transcription of genes associated with an exhausted state such as HAVCR2 and CD244, and downregulate that of effector genes such as STAT4 and CXCR3, which leads to the expression of inhibitory receptors such as PD-1, TIM-3, and inhibition of activating receptors such as CD226. Direct activation of cytotoxic T cells apoptosis is mediated by the activation of FAS, expressed on CD8⁺ T cells, by FAS ligand, expressed on glioblastoma and Treg cells. Underlined are the inhibitory antibodies and molecules that have been used to enhance the immune response against glioblastoma in clinical trials.