MET overexpression contributes to STAT4-PD-L1 signaling activation associated with tumor-associated, macrophages-mediated immunosuppression in primary glioblastomas

Abstract

BackgroundDysregulated receptor tyrosine kinases, such as the mesenchymal-epidermal transition factor (MET), have pivotal role in gliomas. MET and its interaction with the tumor microenvironment have been previously implicated in secondary gliomas. However, the contribution of MET gene to tumor cells’ ability to escape immunosurveillance checkpoints in primary gliomas, especially in glioblastoma (GBM), which is a WHO grade 4 glioma with the worst overall survival, is still poorly understood.MethodsWe investigated the relationship between MET expression and glioma microenvironment by using multiomics data and aimed to understand the potential implications of MET in clinical practice through survival analysis. RNA expression data from a total of 1243 primary glioma samples (WHO grades 2–4) were assembled, incorporating The Cancer Genome Atlas, Chinese Glioma Genome Atlas, and GSE16011 data sets.ResultsPearson’s correlation test from the three data sets indicated that MET showed a robust correlation with programmed death-ligand 1 (PD-L1) and STAT pathways. Western blot analysis revealed that in GBM cell lines (N33 and LN229), PD-L1 and phosphorylated STAT4 were upregulated by MET activation treatment with hepatocyte growth factor and were downregulated on MET suppression by PLB-1001. Tumor tissue microarray analysis indicated a positive correlation between MET and PD-L1 and macrophage-associated markers. Chromatin immunoprecipitation-PCR assay showed enrichment of STAT4 in the PD-L1 DNA. Transwell co-culture and chemotaxis assays revealed that knockdown of MET in GBM cells inhibited macrophage chemotaxis. Moreover, we performed CIBERSORTx and single-cell RNA sequencing data analysis which revealed an elevated number of macrophages in glioma samples with MET overexpression. Kaplan-Meier survival analysis indicated that activation of the MET/STAT4/PD-L1 pathway and upregulation of macrophages were associated with shorter survival time in patients with primary GBM.ConclusionsThese data indicated that the MET-STAT4-PD-L1 axis and tumor-associated macrophages might enforce glioma immune evasion and were associated with poor prognosis in GBM samples, suggesting potential clinical strategies for targeted therapy combined with immunotherapy in patients with primary GBM.

Endogenous Pancreatic Cancer Cell PD-1 Activates MET and Induces Epithelial-Mesenchymal Transition to Promote Cancer Progression

“…In fact, MET overexpression has been detected in nearly two-thirds of PDACs and has been associated with worse clinical outcomes [11]. Interestingly, other recent studies have shown that activated MET and EMT pathways increase tumor-endogenous PD-L1 production [34,35]. These studies, along with our results, identify a potential positive feedback loop and will be explored in future investigations.…”

Engineering neoantigen vaccines to improve cancer personalized immunotherapy

“…Meanwhile, TME, consisting of tumor cells, immune cells, interstitial tissue, and extracellular matrix, was inextricably linked with the development, invasion, and metastasis of tumors. The presence of tumor-associated fibroblasts 116 , tumor-associated macrophages 117 , tumor-associated mast cells 118 , Tregs 119 , and bone marrow-derived suppressor cells (MDSC) 120 helped tumor cells escape immune killing. In recent years, it has been found that tumor-associated neutrophils also had several connections to immune escape.…”

Targeting tumor-associated macrophages for the immunotherapy of glioblastoma: Navigating the clinical and translational landscape

“…The high expression of major histocompatibility complex class II (MHC-II; the canonical lymphocyte-activation gene 3 ligand, LAG3 ligand) on MG can elevate the expression of exhaustion-associated biomarkers (e.g., LAG3) in T cell populations, contributing to the formation of the immunosuppressive TME ( 42 ). Meanwhile, a close correlation between the tumor suppressor protein p53 (TP53) and MG infiltration was identified.…”

“…BMDMs and GBM cells collectively contribute to the immunosuppressive TME of GBM. The abundance of signal transducer and activator of transcription 3 (STAT3) in GBM has been demonstrated to promote AHR expression and cooperate with HIF-1α to increase CD40 levels, which in turn promoted GBM immune evasion and STAT4-mediated PD-L1 upregulation ( 42 , 51 , 55 ). Moreover, multiple factors have been implicated in the recruitment and polarization of BMDMs, including slit guidance ligand 2 (SLIT2) ( 56 ), Notch1 ( 57 ), PTEN ( 58 ), NF1 ( 59 ), TGF-β ( 47 , 60 , 61 ), M-CSF ( 47 , 60 , 61 ), PD-L2 ( 62 ), IL-33 ( 63 ), arginase 1 (ARG1) ( 64 ), CD47 ( 65 ), and CD70 ( 66 ).…”