PD-L1/PD-1 Axis in Glioblastoma Multiforme

Abstract

Glioblastoma (GBM) is the most popular primary central nervous system cancer and has an extremely expansive course. Aggressive tumor growth correlates with short median overall survival (OS) oscillating between 14 and 17 months. The survival rate of patients in a three-year follow up oscillates around 10%. The interaction of the proteins programmed death-1 (PD-1) and programmed cell death ligand (PD-L1) creates an immunoregulatory axis promoting invasion of glioblastoma multiforme cells in the brain tissue. The PD-1 pathway maintains immunological homeostasis and protects against autoimmunity. PD-L1 expression on glioblastoma surface promotes PD-1 receptor activation in microglia, resulting in the negative regulation of T cell responses. Glioblastoma multiforme cells induce PD-L1 secretion by activation of various receptors such as toll like receptor (TLR), epidermal growth factor receptor (EGFR), interferon alpha receptor (IFNAR), interferon-gamma receptor (IFNGR). Binding of the PD-1 ligand to the PD-1 receptor activates the protein tyrosine phosphatase SHP-2, which dephosphorylates Zap 70, and this inhibits T cell proliferation and downregulates lymphocyte cytotoxic activity. Relevant studies demonstrated that the expression of PD-L1 in glioma correlates with WHO grading and could be considered as a tumor biomarker. Studies in preclinical GBM mouse models confirmed the safety and efficiency of monoclonal antibodies targeting the PD-1/PD-L1 axis. Satisfactory results such as significant regression of tumor mass and longer animal survival time were observed. Monoclonal antibodies inhibiting PD-1 and PD-L1 are being tested in clinical trials concerning patients with recurrent glioblastoma multiforme.

TLR-4 Signaling vs. Immune Checkpoints, miRNAs Molecules, Cancer Stem Cells, and Wingless-Signaling Interplay in Glioblastoma Multiforme—Future Perspectives

“…T cells recognize PD-1L and bind it with an adequate PD-1 receptor. The intracellular domain of the receptor consists of an (ITSM) tyrosine-based switch motif that activates an inhibitory cascade [118][119][120][121][122][123][124]. Downsignaling promotes tyrosine phosphatase 2/Zeta-chain-associated protein kinase 7 (SHP-2/Zap 70) interplay, resulting in dephosphorylation and a significant decrease in lymphocytic cytotoxicity and proliferation.…”

Characterization of clinical significance of PD-1/PD-Ls expression and methylation in patients with low grade glioma

“…LGG is the main subtype of gliomas, which characterized with lower aggressiveness and well differentiation than GBM counterpart. A growing number of studies focus on the interplay between glioma and immunity, but most research attach great attentions to the GBM [24][25][26]. LGG seems to be ignored from the field of cancer immunotherapy due to its better prognosis than GBM.…”

Metformin as Potential Therapy for High-Grade Glioma

“…In the analysis of GBM immunology, proteins programmed death-1 (PD-1) and programmed cell death ligand (PD-L1) also play an important role. It is recognized that the disturbances in the expression of these particles increase the aggression and invasiveness of GBM cells in the brain tissue [142]. In their work, Cha et al, showed that metformin could also affect this link in the cancer process.…”