Diverse Macrophages Constituted the Glioma Microenvironment and Influenced by PTEN Status.

Fengqi Zhou,Yongping You,Wei Tian,Yingyi Wang,Minhong Pan,Binbin Wang,Ruilei Yu,Tianfu Yu,Zhiqiang Wu,Xiao Fan,Qinyu Shi

doi:10.3389/fimmu.2022.841404

Abstract

The glioma immune microenvironment (GIM), consisting of glioma cells, stromal cells, and immune cells, accelerates the initiation, development, immune evasion, chemoresistance, and radioresistance of glioblastoma (GBM), whereas the immunosuppressive mechanisms of GBM have not been thoroughly elucidated to date. The glioma data downloaded from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases were used to evaluate the composition of tumor-infiltrating immune cells (TICs) by the CIBERSORT algorithm. RNA-seq datasets from the TCGA and CGGA were used to analyze the relationship between immune scores with patients’ characteristics and TICs, which showed higher ratios of tumor-inhibiting/tumor-promoting signatures (M2/M1 macrophages) along with higher immune scores. The distribution of TICs among different glioma patients and the correlation with hazard ratio (HR) analysis suggested that M2 macrophages were abundant in malignant gliomas and indicated an unfavorable prognosis. We further analyzed TCGA cases with available mutation and copy-number alteration information, which showed that the status of PTEN could influence the immune microenvironment of glioma patients. Tissue microarrays of 39 GBM patients were carried out to confirm the clinical significance of PTEN and macrophage markers. We found that the high expression of PTEN was associated with a more extended survival period of glioma patients, positively correlated with M2 macrophages and negatively with M1 macrophages. Transwell and flow cytometry analyses demonstrated that PTEN status could prevent M1 to M2 polarization and M2 macrophage recruitment of gliomas in vitro. The newly discovered immunoregulatory activity of PTEN opens innovative avenues for investigations relevant to counteracting cancer development and progression.

Highlights

Gliomas comprise nearly four-fifths of all common malignant central nervous system tumors, which include low-grade glioma (LGG) and glioblastoma (GBM) [1]
We found a positive correlation between glioma immune scores and clinical or molecular characteristics, including age, grade, and histology
We noticed that B cells naive, B cells memory, plasma cells, T cells CD8, Tregs, NK cells resting, monocytes, macrophages M1, and neutrophils were negatively correlated with the immune score in the The Cancer Genome Atlas (TCGA), while B cells naive, plasma cells, T cells CD4, T cells, NK cells active, macrophages M1, dendritic cells activated, and neutrophils were negatively correlated with the immune score in the Chinese Glioma Genome Atlas (CGGA) as well

Summary

Introduction

Gliomas comprise nearly four-fifths of all common malignant central nervous system tumors, which include low-grade glioma (LGG) and glioblastoma (GBM) [1]. LGG, according to the criteria established by the World Health Organization (WHO), defined as a lower grade (I–III), has a more favorable prognosis. Given that multiple components composed the glioma microenvironment, including blood vessels, parenchyma cells, extracellular matrix, soluble factors, and infiltrating immune cells [7, 8], tumor-associated macrophages (TAMs) are enriched in GBMs, serving as an essential element of the tumor microenvironment in GBM and playing crucial roles in supporting tumor growth [9, 10], suggesting that targeting TAMs may improve tumor outcome. M2 macrophages play immune-suppressive roles via promoting tumor development [12]. M2 macrophages have a remarkable effect on the development of GBMs, the mechanisms underlying the program and maintenance of M2 macrophages in the glioma microenvironment remain unknown

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Conclusion