PD-L1/PD-1 axis in GBM

Polymorphic glioblastoma (GBM) is the most common primary central nervous system malignanciesCurrently, the standard treatment is the maximum surgical excision and combination of TMZ radiation chemotherapyThe median total survival (OS) of GBM was short (14-17 months) and the three-year survival rate was about 10%, which was related to the aggressiveness of the tumorGBM has the ability to remove CD4-T cells from tumor tissue and to react with cytotoxicity associated with the effects of Th1The immune response can be transformed into chronic inflammation mediated by Th17 cells, creating conditions for tumor attackThe central nervous system (CNS) has a blood-brain barrier (BBB) and a lack of typical lymphatic system, so CNS was previously considered an immune organRecent studies have shown a special link between the central nervous system and the deep lymph nodes of the neck: antigens and T-cells are transferred through passages containing cerebrospinal fluidAntigen-presented cells (APCs), such as small glial cells, macrophages, and dendritic cells activate T cells to reach the central nervous system through gaps around the blood vessels and identify tumor cells, a process controlled by the programmed cell death factor 1 (programmed death-1, PD-1)/programmed cell death ligand 1 (programmed cell death ligand, PD-L1) axis; Jakub Litak of the Center for Immunology at Lublin Medical University in Poland, et al., published a review of the PD-L1/PD-1 axis in GBM in October 2019 in the journal International Journal of Molecular Sciencesmethod sedative synod 1 (programmed death-1, PD-1) protein and programmatic cell death ligand 1 (programmed cell death ligand, PD-L1) protein interact to produce an immune regulatory axis that promotes the invasion of GBM cells in brain tissuePhysiologically, the main function of PD-1 is to inhibit the anti-tumor activity of T cells and increase the activation of regulatory cells (Tregs), thereby limiting T-cell response and preventing immune hypertrophicizationThe PD-L1/PD-1 axis maintains immune stability and prevents autoimmunePD-L1 is expressed and secreted by tumor cells, APC, B lymphocytes and essential cellsIt induces T-apoptosis or deactivation and regulates inflammation in situPD-L1 binds to the corresponding PD-1 receptor to activate the tyrosine phosphatase SHP-2 protein, which causes Zap 70 dephosphateing (Figure 1), thereby inhibiting T-cell proliferation and reducing the cytotoxicity of lymphocytesFigure 1GBM cell-induced immunomodulation Programal cell death ligand 1 (PD-L1) secretes to suppress the immune response and block the T-cell response PD-1: programocellular death factor-1; MHC: primary tissue-compatible complex; TCR: T cell receptor; APC: antigen-presented cell PD-L1 overexpression in GBM cells and small glial cells can promote the effective binding of PD-L1 to PD-1, which causes negative regulation of the immune response This negative regulation mainly affects t-cell response GBM increases the surface expression of immune checkpoint molecules (e.g PD-L1/PD-1) to promote immunosuppression Other studies have shown that glioma cells are the main expression of PD-L1, and there is evidence that the presence of PD-L1 in glioma cells is associated with WHO grading and is considered to be a biomarker of glioma cells GBM cells can induce PD-L1 secretion by activating various receptors, such as toll receptor (TLR), epidermal growth factor receptor (epidermal growth factor receptor, EGFR), interferon alpha receptor (interferon alpha receptor, IFNAR), interferon gamma receptor (interferon receptor, IFNGR) the results of the study studies have found that (1) TLR is endogenous expression in glioma cells TLR in glioma cells is signal-dyed by activating two main pathways of myelin differentiation factor 88 (myeloid differentiation factor 88, MyD88), one of which is non-dependent MyD88 and the other is dependent MyD88 The former initiates The Transcription of the PD-L1 gene; (2) Improper activation of EGFR leads to apoptosis changes or tumor angiogenesis, tumor necrosis or proliferation and therapeutic resistance, indicating that the receptor disorder is related to various biological changes in cancer Studies have shown that PD-1 activation is interdependent with EGFR downstream signal transduction Increased Activity of EGFR promotes the expression of PD-L1 Experiments in GBM mouse models showed that the interaction of eGFR progenitor cancer genes caused the loss of phosphatase genes (PTEN), while PTEN deficiency contributed to an increase in the expression of PD-L1 (3) Glioblastoma is highly susceptible to the development of peripheral tissues and new angiogenesis, while the PD-L1/PD-1 axis has anangiogenesis effect that regulates VEGF level mediated Studies have confirmed that PD-L1 expression levels are closely related to VEGF expression levels in patients with primary gliomas However, it is worth noting that there are studies that show a negative correlation between VEGF-related genes and PD-L1 activity, so further research is needed to thoroughly understand the relationship between PD-L1/PD-1 axis and angiogenesis (4) Interferon-induced intracellular signals have a negative regulatory effect on the anti-tumor immune response of gliomas IFN-xenon stimulation results in an increase in JAK2/STAT1/IRF1, so the expression of increased PD-L1 can be used as a characteristic signal transmission element for type II interferon IFN-Xenon stimulates THE STAT3, STAT2, and IRF9 axes, which are more typical type I interferon stimulation (Figure 2) Figure 2 GBM induces PD-L1 secretion Multiple activation pathways (TLR, EGFR, IFNAR, IFNGR) promote PD-L1 expression: (1) Toll-like receptor (TLR) pathway: pathogen-related molecular patterns (PAMPs), necrosis, heat shock protein (HSP) as activations of The TLR myelin differentiation factor 88 (MyD88) dependence pathway, transmitted through TRAF6/MEK/ERK/NFB (2) Epidermal Growth Factor Receptor (EGFR) Pathway: TGF alpha/EGF/VGF/MUTATION OF RECEPTOR acts as an activator for EGFR pathway signals via MEK/ERK (STAT-1)/NF-B (3) IFNAR pathway: interferon (IFN-alpha) and IFN-beta as activators of IFNAR pathway signals, through MXA gene transcription, the formation of non-classical MHC, promote PD-1L transcription, and induce endogenous interferon (4) IFNGR pathway: IFN-Xenon, as an activator for IIFNGR pathway signal transduction, has a regulatory function for transcribed PD-1L mRNA via JAK/STAT-1/MEK/ERK/IRF-1 and PI3K/PIP3/AKT/m6K1 clinically, monoclonal antibodies (monoclonal antibodies, mAbs) have a transformational effect on the immunotherapy of tumors mAbs can block receptors of immune-effect cells or ligands on tumor cells and auxiliary cells such as APC Preclinical GBM mouse model studies have confirmed the safety and effectiveness of monoclonal antibodies targeted at PD-L1/PD-1 axis, and satisfactory results have been observed, such as the apparent subsidence of tumors and the prolonged survival time of tumor-carrying animals Currently, clinical trials involving patients with recurrent polymorphic glioblastoma are being tested to inhibit monoclonal antibodies that inhibit PD-1 and PD-L1 conclusions the authors concluded that GBM is highly resistant to standard therapies, and that their invasive and short OS characteristics are still uncontrollable; Activate PD-L1/PD-1 to remove the pathway of immune escape from dependent glioma cells Blocking the interaction between PD-L1 and PD-1 rebuilds immunity to GBM Recent clinical studies have shown that PD-L1/PD-1 inhibitors are effective in mitigating tumor progression Although the trial did not confirm the extension of OS, these inhibitors may benefit GBM patients differently if used in combination with standard treatments.