Identification of CCL4 as an Immune-Related Prognostic Biomarker Associated With Tumor Proliferation and the Tumor Microenvironment in Clear Cell Renal Cell Carcinoma

The last decade has witnessed revolutionary advances taken in immunotherapy for various malignant tumors. However, immune-related molecules and their characteristics in the prediction of clinical outcomes and immunotherapy response in clear cell renal cell carcinoma (ccRCC) remain largely unclear. C...

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Autores principales:	Lu Zhang, Mengzhao Zhang, Lu Wang, Jianlong Li, Tao Yang, Qiuya Shao, Xiao Liang, Minghai Ma, Nan Zhang, Minxuan Jing, Rundong Song, Jinhai Fan
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	CCL4 tumor proliferation immune infiltration tumor microenvironment immune checkpoints clear cell renal cell carcinoma Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/682895e2e2d84a859f1a0827826e7a6f
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spelling	oai:doaj.org-article:682895e2e2d84a859f1a0827826e7a6f2021-11-30T18:58:50ZIdentification of CCL4 as an Immune-Related Prognostic Biomarker Associated With Tumor Proliferation and the Tumor Microenvironment in Clear Cell Renal Cell Carcinoma2234-943X10.3389/fonc.2021.694664https://doaj.org/article/682895e2e2d84a859f1a0827826e7a6f2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.694664/fullhttps://doaj.org/toc/2234-943XThe last decade has witnessed revolutionary advances taken in immunotherapy for various malignant tumors. However, immune-related molecules and their characteristics in the prediction of clinical outcomes and immunotherapy response in clear cell renal cell carcinoma (ccRCC) remain largely unclear. C-C Motif Chemokine Ligand 4 (CCL4) was extracted from the intersection analysis of common differentially expressed genes (DEGs) of four microarray datasets from the Gene Expression Omnibus database and immune-related gene lists in the ImmPort database using Cytoscape plug-ins and univariate Cox regression analysis. Subsequential analysis revealed that CCL4 was highly expressed in ccRCC patients, and positively correlated with multiple clinicopathological characteristics, such as grade, stage and metastasis, while negatively with overall survival (OS). We performed gene set enrichment analysis (GSEA) and gene set variant analysis (GSVA) with gene sets coexpressed with CCL4, and observed that gene sets positively related to CCL4 were enriched in tumor proliferation and immune-related pathways while metabolic activities in the negatively one. To further explore the correlation between CCL4 and immune-related biological process, the CIBERSORT algorithm, ESTIMATE method, and tumor mutational burden (TMB) score were employed to evaluate the tumor microenvironment (TME) characteristics of each sample and confirmed that high CCL4 expression might give rise to high immune cell infiltration. Moreover, correlation analysis revealed that CCL4 was positively correlated with common immune checkpoint genes, such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and lymphocyte activating 3 (LAG3). Overall, this study demonstrated that CCL4 might serve as a potential immune-related prognostic biomarker to predict clinical outcomes and immunotherapy response in ccRCC. Moreover, CCL4 might contribute to TME modulation, indicating the mechanism CCL4 involved in tumor proliferation and metastasis, which could provide novel therapeutic perceptions for ccRCC patients.Lu ZhangMengzhao ZhangLu WangJianlong LiTao YangQiuya ShaoXiao LiangMinghai MaNan ZhangMinxuan JingRundong SongJinhai FanJinhai FanFrontiers Media S.A.articleCCL4tumor proliferationimmune infiltrationtumor microenvironmentimmune checkpointsclear cell renal cell carcinomaNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CCL4 tumor proliferation immune infiltration tumor microenvironment immune checkpoints clear cell renal cell carcinoma Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	CCL4 tumor proliferation immune infiltration tumor microenvironment immune checkpoints clear cell renal cell carcinoma Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Lu Zhang Mengzhao Zhang Lu Wang Jianlong Li Tao Yang Qiuya Shao Xiao Liang Minghai Ma Nan Zhang Minxuan Jing Rundong Song Jinhai Fan Jinhai Fan Identification of CCL4 as an Immune-Related Prognostic Biomarker Associated With Tumor Proliferation and the Tumor Microenvironment in Clear Cell Renal Cell Carcinoma
description	The last decade has witnessed revolutionary advances taken in immunotherapy for various malignant tumors. However, immune-related molecules and their characteristics in the prediction of clinical outcomes and immunotherapy response in clear cell renal cell carcinoma (ccRCC) remain largely unclear. C-C Motif Chemokine Ligand 4 (CCL4) was extracted from the intersection analysis of common differentially expressed genes (DEGs) of four microarray datasets from the Gene Expression Omnibus database and immune-related gene lists in the ImmPort database using Cytoscape plug-ins and univariate Cox regression analysis. Subsequential analysis revealed that CCL4 was highly expressed in ccRCC patients, and positively correlated with multiple clinicopathological characteristics, such as grade, stage and metastasis, while negatively with overall survival (OS). We performed gene set enrichment analysis (GSEA) and gene set variant analysis (GSVA) with gene sets coexpressed with CCL4, and observed that gene sets positively related to CCL4 were enriched in tumor proliferation and immune-related pathways while metabolic activities in the negatively one. To further explore the correlation between CCL4 and immune-related biological process, the CIBERSORT algorithm, ESTIMATE method, and tumor mutational burden (TMB) score were employed to evaluate the tumor microenvironment (TME) characteristics of each sample and confirmed that high CCL4 expression might give rise to high immune cell infiltration. Moreover, correlation analysis revealed that CCL4 was positively correlated with common immune checkpoint genes, such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and lymphocyte activating 3 (LAG3). Overall, this study demonstrated that CCL4 might serve as a potential immune-related prognostic biomarker to predict clinical outcomes and immunotherapy response in ccRCC. Moreover, CCL4 might contribute to TME modulation, indicating the mechanism CCL4 involved in tumor proliferation and metastasis, which could provide novel therapeutic perceptions for ccRCC patients.
format	article
author	Lu Zhang Mengzhao Zhang Lu Wang Jianlong Li Tao Yang Qiuya Shao Xiao Liang Minghai Ma Nan Zhang Minxuan Jing Rundong Song Jinhai Fan Jinhai Fan
author_facet	Lu Zhang Mengzhao Zhang Lu Wang Jianlong Li Tao Yang Qiuya Shao Xiao Liang Minghai Ma Nan Zhang Minxuan Jing Rundong Song Jinhai Fan Jinhai Fan
author_sort	Lu Zhang
title	Identification of CCL4 as an Immune-Related Prognostic Biomarker Associated With Tumor Proliferation and the Tumor Microenvironment in Clear Cell Renal Cell Carcinoma
title_short	Identification of CCL4 as an Immune-Related Prognostic Biomarker Associated With Tumor Proliferation and the Tumor Microenvironment in Clear Cell Renal Cell Carcinoma
title_full	Identification of CCL4 as an Immune-Related Prognostic Biomarker Associated With Tumor Proliferation and the Tumor Microenvironment in Clear Cell Renal Cell Carcinoma
title_fullStr	Identification of CCL4 as an Immune-Related Prognostic Biomarker Associated With Tumor Proliferation and the Tumor Microenvironment in Clear Cell Renal Cell Carcinoma
title_full_unstemmed	Identification of CCL4 as an Immune-Related Prognostic Biomarker Associated With Tumor Proliferation and the Tumor Microenvironment in Clear Cell Renal Cell Carcinoma
title_sort	identification of ccl4 as an immune-related prognostic biomarker associated with tumor proliferation and the tumor microenvironment in clear cell renal cell carcinoma
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/682895e2e2d84a859f1a0827826e7a6f
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Identification of CCL4 as an Immune-Related Prognostic Biomarker Associated With Tumor Proliferation and the Tumor Microenvironment in Clear Cell Renal Cell Carcinoma

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