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

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

doi:10.3389/fsurg.2021.775194

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

Front Surg. 2022 Feb 3:8:775194. doi: 10.3389/fsurg.2021.775194. eCollection 2021.

Authors

Yong Xiao¹, Kun Yang¹, Zhen Wang¹, Mengjie Zhao², Yanxiang Deng³, Wei Ji^{1

4}, Yuanjie Zou¹, Chunfa Qian¹, Yong Liu¹, Hong Xiao², Hongyi Liu¹

Affiliations

¹ Department of Neurosurgery, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China.
² Department of Neuro-Psychiatric Institute, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China.
³ Department of Biomedical Engineering, Yale University, New Haven, CT, United States.
⁴ Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China.

Abstract

Background: Glioma 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.

Methods: In 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.

Results: CD44 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.

Conclusion: Our 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.

Keywords: CD44; M2; glioma; immunosuppression; single cell; spatial; tumor-associated macrophage.