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

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

JOURNAL=Frontiers in Surgery

VOLUME=8

YEAR=2022

URL=https://www.frontiersin.org/journals/surgery/articles/10.3389/fsurg.2021.775194

DOI=10.3389/fsurg.2021.775194

ISSN=2296-875X

ABSTRACT=<sec><title>Background</title><p>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 <italic>CD44</italic> in glioma, we explored its function at bulk-transcriptome, spatial and single-cell transcriptome levels.</p></sec><sec><title>Methods</title><p>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<italic>-PD-1</italic> immunotherapy accessed through GSE121810, and single-cell RNA-seq data of GBM under accession <ext-link ext-link-type="DDBJ/EMBL/GenBank" xlink:href="GSE103224" xmlns:xlink="http://www.w3.org/1999/xlink">GSE103224</ext-link> were enrolled in this study. <italic>CD44</italic>-specific findings were further analyzed by R language.</p></sec><sec><title>Results</title><p><italic>CD44</italic> is positively correlated with WHO grade of malignancy and is negatively related to prognosis in glioma. Meanwhile, <italic>CD44</italic> predominantly expresses in GBM mesenchymal subtype, and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses reveal that <italic>CD44</italic> positively coexpressed genes are closely related to glioma immunity. Moreover, <italic>CD44</italic>+ 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 <italic>CD44</italic> in GBM. <italic>CD44</italic>+ malignant tumor cells are in mesenchymal-1-like (MES1-like) cellular state, and <italic>CD44</italic>+ TAMs are in M2 phenotype. <italic>CD44</italic>+ T cells have high expression of both <italic>PD-1</italic> and <italic>PD-L1</italic>. <italic>CD44</italic> and its directly interacted inhibitory immunomodulators are upregulated in patients with nonresponder recurrent GBM treated with <italic>PD-1</italic> blockade therapy.</p></sec><sec><title>Conclusion</title><p>Our work demonstrates that <italic>CD44</italic>, a new M2 TAM biomarker, is involved in immune suppressor and promote glioma progression in glioma microenvironment. These results expand our understanding of <italic>CD44</italic>-specific clinical and immune features in glioma.</p></sec>