Glioma-Associated Stromal Cells Stimulate Glioma Malignancy by Regulating the Tumor Immune Microenvironment

Abstract

BackgroundThe glioma-associated stromal cell (GASC) is a recently identified type of cell in the glioma microenvironment and may be a prognostic marker for glioma. However, the potential mechanisms of GASCs in the glioma microenvironment remain largely unknown. In this work, we aimed to explore the mechanisms of GASCs in gliomas, particularly in high-grade gliomas (HGG).MethodsWe used glioma datasets from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). We utilized the Single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm to discriminate between patients with high or low GASC composition. The xCELL and CIBERSORT algorithms were used to analyze the composition of stromal cells and immune cells. Risk score and a nomogram model were constructed for prognostic prediction of glioma.ResultsWe observed for the first time that the levels of M2 macrophages and immune checkpoints (PD-1, PD-L1, PD-L2, TIM3, Galectin-9, CTLA-4, CD80, CD86, CD155, and CIITA) were significantly higher in the high GASC group and showed positive correlation with the GASC score in all glioma population and the HGG population. Copy number variations of DR3 and CIITA were higher in the high-GASC group. THY1, one of the GASC markers, exhibited lower methylation in the high GASC group. The constructed risk score was an independent predictor of glioma prognostics. Finally, a credible nomogram based on the risk score was established.ConclusionsGASCs stimulate glioma malignancy through the M2 macrophage, and are associated with the level of immune checkpoints in the glioma microenvironment. The methylation of THY1 could be used as prognostic indicator and treatment target for glioma. However, further studies are required to verify these findings.

Differential expression of PD‑L1 and PD‑L2 is associated with the tumor microenvironment of TILs and M2 TAMs and tumor differentiation in non‑small cell lung cancer

“…Recent studies show that other signals derived from macrophages, such as TNF-α, VEGF and CXCL8, can induce PD-L1 expression ( 41 – 43 ). In addition, previous studies report that macrophages can induce not only PD-L1 expression, but also PD-L2 expression ( 44 , 45 ).…”

Identification and Validation of the Pyroptosis-Related Molecular Subtypes of Lung Adenocarcinoma by Bioinformatics and Machine Learning

“…The level of immune cell infiltration in the LUAD samples was quantified by inferencing the infiltrating cells in the tumor microenvironment (TME). We applied integrated bioinformatics methods, including MCPcounter, xCell, quanTIseq, CIBERSORTx, single-sample gene set enrichment analysis (GSEA) to evaluate differences of immune status among different molecular subtypes ( Finotello et al, 2019 ; Cai et al, 2021 ; Yuan et al, 2021 ). Furthermore, the ‘‘pRRophetic’’ R package was used to predict the chemotherapy response of each sample based on Genomics of Drug Sensitivity in Cancer (GDSC) 3 , and the correlation between molecular subtypes and immune checkpoint genes was analyzed ( Geeleher et al, 2014 ; Kuang et al, 2021 ).…”

A Novel Prognostic Tool for Glioma Based on Enhancer RNA-Regulated Immune Genes

“…Single-sample gene set enrichment analysis (ssGSEA) was implemented to obtain a second estimate of immune cell infiltration ( Barbie et al, 2009 ). Other immunocyte infiltration algorithms were also taken into account in our research, including xCell and Tumor Immune Estimation Resource (TIMER) ( Aran et al, 2017 ; Li et al, 2017 ; Cai et al, 2021 ). As an important gene family related to immune functionality, human leukocyte antigen (HLA) was compared to uncover additional differences in the TME.…”

“…To overcome this problem, we used TERT gene expression as a proxy for TERTp mutation status ( Galbraith et al, 2020 ). Traditionally, MGMTp methylation status is an important common biomarker, but the TCGA cohort could not directly provide relevant information, compelling the use of MGMT methylation level to represent MGMTp status ( Cai et al, 2021 ).…”

“…In recent years, immunotherapy has emerged as a promising approach for treating patients with malignant tumors including gliomas ( Jahan et al, 2018 ). However, the clinical benefits may outweigh the costs only in a small fraction of glioma patients, due to the “cold tumor” character and complex tumor microenvironment (TME) of this malignancy ( Wang et al, 2020 ; Cai et al, 2021 ). Although several studies have revealed a function for immune-related genes (IRGs) in immune cell infiltration, tumorigenesis, and tumor prognosis ( Najima et al, 2016 ), their exact role and regulators remain unclear ( Lou et al, 2020 ).…”