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CCR5 as a Prognostic Factor in Lower-Grade Glioma is Involved in the Remodeling of the Tumor Microenvironment
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 des...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294513/ https://www.ncbi.nlm.nih.gov/pubmed/35865011 http://dx.doi.org/10.3389/fgene.2022.874896 |
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author | Wang, Fang Tao, Zhennan Tian, Zhen Jin, Jiaqi Dong, Jiawei Dai, Yuxiang Yu, Wanli Tang, Bin Hu, Shaoshan |
author_facet | Wang, Fang Tao, Zhennan Tian, Zhen Jin, Jiaqi Dong, Jiawei Dai, Yuxiang Yu, Wanli Tang, Bin Hu, Shaoshan |
author_sort | Wang, Fang |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9294513 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92945132022-07-20 CCR5 as a Prognostic Factor in Lower-Grade Glioma is Involved in the Remodeling of the Tumor Microenvironment Wang, Fang Tao, Zhennan Tian, Zhen Jin, Jiaqi Dong, Jiawei Dai, Yuxiang Yu, Wanli Tang, Bin Hu, Shaoshan Front Genet Genetics 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. Frontiers Media S.A. 2022-07-05 /pmc/articles/PMC9294513/ /pubmed/35865011 http://dx.doi.org/10.3389/fgene.2022.874896 Text en Copyright © 2022 Wang, Tao, Tian, Jin, Dong, Dai, Yu, Tang and Hu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics Wang, Fang Tao, Zhennan Tian, Zhen Jin, Jiaqi Dong, Jiawei Dai, Yuxiang Yu, Wanli Tang, Bin Hu, Shaoshan CCR5 as a Prognostic Factor in Lower-Grade Glioma is Involved in the Remodeling of the Tumor Microenvironment |
title | CCR5 as a Prognostic Factor in Lower-Grade Glioma is Involved in the Remodeling of the Tumor Microenvironment |
title_full | CCR5 as a Prognostic Factor in Lower-Grade Glioma is Involved in the Remodeling of the Tumor Microenvironment |
title_fullStr | CCR5 as a Prognostic Factor in Lower-Grade Glioma is Involved in the Remodeling of the Tumor Microenvironment |
title_full_unstemmed | CCR5 as a Prognostic Factor in Lower-Grade Glioma is Involved in the Remodeling of the Tumor Microenvironment |
title_short | CCR5 as a Prognostic Factor in Lower-Grade Glioma is Involved in the Remodeling of the Tumor Microenvironment |
title_sort | ccr5 as a prognostic factor in lower-grade glioma is involved in the remodeling of the tumor microenvironment |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294513/ https://www.ncbi.nlm.nih.gov/pubmed/35865011 http://dx.doi.org/10.3389/fgene.2022.874896 |
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