CCR5 as a Prognostic Factor in Lower-Grade Glioma is Involved in the Remodeling of the Tumor Microenvironment

Fang Wang; Zhennan Tao; Zhen Tian; Jiaqi Jin; Jiawei Dong; Yuxiang Dai; Wanli Yu; Bin Tang; Shaoshan Hu

doi:10.3389/fgene.2022.874896

CCR5 as a Prognostic Factor in Lower-Grade Glioma is Involved in the Remodeling of the Tumor Microenvironment

Front Genet. 2022 Jul 5:13:874896. doi: 10.3389/fgene.2022.874896. eCollection 2022.

Authors

Fang Wang^{1

2}, Zhennan Tao³, Zhen Tian⁴, Jiaqi Jin^{1

2}, Jiawei Dong^{1

2}, Yuxiang Dai³, Wanli Yu⁵, Bin Tang⁵, Shaoshan Hu^{1

2}

Affiliations

¹ Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
² Department of Neurosurgery, Emergency Medicine Center, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, China.
³ Department of Neurosurgery, the Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China.
⁴ Department of Minimally Invasive Interventional Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁵ Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China.

Abstract

Background: Lower-grade gliomas (LGGs) carry a high risk of malignant transformation, leading to severe neurologic deterioration and ultimately, death. The tumor microenvironment (TME) plays an essential role in tumor maintenance, progression, and immunotherapy resistance. Therefore, the LGG TME deserves comprehensive exploration for a novel therapeutic target. Methods: The ESTIMATE algorithm was used to estimate infiltrating stromal and immune cells of LGG patients obtained from the Cancer Genome Atlas (TCGA) database. Kaplan-Meier analysis was performed to classify survival differences. TME-related differentially expressed genes were identified between the low- and high-immune/stromal groups. Hub genes were screened by constructing protein-protein interaction networks and performing the Cox regression analysis. Differential analysis, survival analysis, gene set enrichment analysis, and clinical relevance analysis specific to hub genes were evaluated by using the TCGA and the Chinese Glioma Genome Atlas datasets, and the results were validated by qRT-PCR, Western blotting, and immunohistochemistry in tissues from LGG patients. Results: The immune and stromal components in TME were negatively related to patient prognosis. Differentially expressed genes sharing immune score and stromal score were mainly involved in the immune response. C-C chemokine receptor type 5 (CCR5), as only a hub gene, was significantly higher in LGG patients than normal patients and negatively correlated with the prognosis of patients. High-expression CCR5 was positively related to immune-related and tumor progression pathways. CCR5 protein expression was higher in LGG with isocitrate dehydrogenase wildtype. Validated results showed that CCR5 was upregulated in LGG tissues at mRNA and protein levels and could affect immune cell infiltration. These results suggested that CCR5 was a potential indicator for the status of TME. Conclusion: Glioma cells remodel the immune microenvironment through the high expression of CCR5 and lead to a poor prognosis in patients with LGG. The inhibition of CCR5 may contribute to the efficacy of LGG immunotherapy.

Keywords: CCR5; LGG; glioma; immunological biomarker; tumor microenvironment.