CD44-Mediated Poor Prognosis in Glioma Is Associated With M2-Polarization of Tumor-Associated Macrophages and Immunosuppression.

Yong Xiao,Wei Ji,Mengjie Zhao,Kun Yang,Hong Xiao,Zhen Wang,Yuanjie Zou,Yong Liu,Chunfa Qian,Hongyi Liu,Yanxiang Deng

doi:10.3389/fsurg.2021.775194

Abstract

BackgroundGlioma is the most common primary brain tumor with a poor prognosis. Key genes that are negatively related to prognosis may provide the therapy targets to cure glioma. To clarify the role of CD44 in glioma, we explored its function at bulk-transcriptome, spatial and single-cell transcriptome levels.MethodsIn total, expression profiles with survival data of whole-grade glioma from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), RNA-seq data with anatomic information of glioblastoma (GBM) from the Ivy Glioblastoma Atlas Project, RNA-sequencing (RNA-seq) data from recurrent GBM receiving adjuvant anti-PD-1 immunotherapy accessed through GSE121810, and single-cell RNA-seq data of GBM under accession GSE103224 were enrolled in this study. CD44-specific findings were further analyzed by R language.ResultsCD44 is positively correlated with WHO grade of malignancy and is negatively related to prognosis in glioma. Meanwhile, CD44 predominantly expresses in GBM mesenchymal subtype, and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses reveal that CD44 positively coexpressed genes are closely related to glioma immunity. Moreover, CD44+ cells mainly distribute in perinecrotic region with high expression of immune factors. At single-cell resolution, only malignant tumor cells, tumor-associated macrophages (TAMs), and T cells express CD44 in GBM. CD44+ malignant tumor cells are in mesenchymal-1-like (MES1-like) cellular state, and CD44+ TAMs are in M2 phenotype. CD44+ T cells have high expression of both PD-1 and PD-L1. CD44 and its directly interacted inhibitory immunomodulators are upregulated in patients with nonresponder recurrent GBM treated with PD-1 blockade therapy.ConclusionOur work demonstrates that CD44, a new M2 TAM biomarker, is involved in immune suppressor and promote glioma progression in glioma microenvironment. These results expand our understanding of CD44-specific clinical and immune features in glioma.

Highlights

The most common primary brain tumor in adults is glioma
To answer the question whether CD44 is involved in malignant progress of glioma, we compared its expression level in different WHO grades, IDH types, 1p19q states, and recurrent status in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) glioma mRNA-seq datasets
CD44 expression in both low-grade glioma (LGG) and glioblastoma (GBM) is higher than normal brain tissues, which means CD44 plays a role in glioma tumorigenesis (Figure 1A)

Summary

Introduction

The most common primary brain tumor in adults is glioma. The chimeric antigen receptor (CAR)T cell therapy succeeds in some malignancies, it does not work well in patients with glioma to improve OS and is still at an early clinical investigation stage [4]. Given these clinical challenges of glioma, there is a considerable interest in exploring the molecular mechanisms related to the short survival of patients with glioma, which may be the new therapy targets for glioma. Glioma is the most common primary brain tumor with a poor prognosis. To clarify the role of CD44 in glioma, we explored its function at bulk-transcriptome, spatial and single-cell transcriptome levels

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Results

Discussion

Conclusion