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Identification of fatty acid metabolism–related molecular subtype biomarkers and their correlation with immune checkpoints in cutaneous melanoma

PURPOSE: Fatty acid metabolism (FAM) affects the immune phenotype in a metabolically dynamic tumor microenvironment (TME), but the use of FAM-related genes (FAMGs) to predict the prognosis and immunotherapy response of cutaneous melanoma (CM) patients has not been investigated. In this study, we aim...

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Autores principales: Xu, Yujian, Chen, Youbai, Jiang, Weiqian, Yin, Xiangye, Chen, Dongsheng, Chi, Yuan, Wang, Yuting, Zhang, Julei, Zhang, Qixu, Han, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9716430/
https://www.ncbi.nlm.nih.gov/pubmed/36466837
http://dx.doi.org/10.3389/fimmu.2022.967277
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author Xu, Yujian
Chen, Youbai
Jiang, Weiqian
Yin, Xiangye
Chen, Dongsheng
Chi, Yuan
Wang, Yuting
Zhang, Julei
Zhang, Qixu
Han, Yan
author_facet Xu, Yujian
Chen, Youbai
Jiang, Weiqian
Yin, Xiangye
Chen, Dongsheng
Chi, Yuan
Wang, Yuting
Zhang, Julei
Zhang, Qixu
Han, Yan
author_sort Xu, Yujian
collection PubMed
description PURPOSE: Fatty acid metabolism (FAM) affects the immune phenotype in a metabolically dynamic tumor microenvironment (TME), but the use of FAM-related genes (FAMGs) to predict the prognosis and immunotherapy response of cutaneous melanoma (CM) patients has not been investigated. In this study, we aimed to construct FAM molecular subtypes and identify key prognostic biomarkers in CM. METHODS: We used a CM dataset in The Cancer Genome Atlas (TCGA) to construct FAM molecular subtypes. We performed Kaplan–Meier (K-M) analysis, gene set enrichment analysis (GSEA), and TME analysis to assess differences in the prognosis and immune phenotype between subtypes. We used weighted gene co-expression network analysis (WGCNA) to identify key biomarkers that regulate tumor metabolism and immunity between the subtypes. We compared overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS) between CM patients with high or low biomarker expression. We applied univariable and multivariable Cox analyses to verify the independent prognostic value of the FAM biomarkers. We used GSEA and TME analysis to investigate the immune-related regulation mechanism of the FAM subtype biomarker. We evaluated the immune checkpoint inhibition (ICI) response and chemotherapy sensitivity between CM patients with high or low biomarker expression. We performed real-time fluorescent quantitative PCR (qRT-PCR) and semi-quantitative analysis of the immunohistochemical (IHC) data from the Human Protein Atlas to evaluate the mRNA and protein expression levels of the FAM biomarkers in CM. RESULTS: We identified 2 FAM molecular subtypes (cluster 1 and cluster 2). K-M analysis showed that cluster 2 had better OS and PFS than cluster 1 did. GSEA showed that, compared with cluster 1, cluster 2 had significantly upregulated immune response pathways. The TME analysis indicated that immune cell subpopulations and immune functions were highly enriched in cluster 2 as compared with cluster 1. WGCNA identified 6 hub genes (ACSL5, ALOX5AP, CD1D, CD74, IL4I1, and TBXAS1) as FAM biomarkers. CM patients with high expression levels of the six biomarkers had better OS, PFS, and DSS than those with low expression levels of the biomarkers. The Cox regression analyses verified that the 6 FAM biomarkers can be independent prognostic factors for CM patients. The single-gene GSEA showed that the high expression levels of the 6 genes were mainly enriched in T-cell antigen presentation, the PD-1 signaling pathway, and tumor escape. The TME analysis confirmed that the FAM subtype biomarkers were not only related to immune infiltration but also highly correlated with immune checkpoints such as PD-1, PD-L1, and CTLA-4. TIDE scores confirmed that patients with high expression levels of the 6 biomarkers had worse immunotherapy responses. The 6 genes conveyed significant sensitivity to some chemotherapy drugs. qRT-PCR and IHC analyses verified the expression levels of the 6 biomarkers in CM cells. CONCLUSION: Our FAM subtypes verify that different FAM reprogramming affects the function and phenotype of infiltrating immune cells in the CM TME. The FAM molecular subtype biomarkers can be independent predictors of prognosis and immunotherapy response in CM patients.
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spelling pubmed-97164302022-12-03 Identification of fatty acid metabolism–related molecular subtype biomarkers and their correlation with immune checkpoints in cutaneous melanoma Xu, Yujian Chen, Youbai Jiang, Weiqian Yin, Xiangye Chen, Dongsheng Chi, Yuan Wang, Yuting Zhang, Julei Zhang, Qixu Han, Yan Front Immunol Immunology PURPOSE: Fatty acid metabolism (FAM) affects the immune phenotype in a metabolically dynamic tumor microenvironment (TME), but the use of FAM-related genes (FAMGs) to predict the prognosis and immunotherapy response of cutaneous melanoma (CM) patients has not been investigated. In this study, we aimed to construct FAM molecular subtypes and identify key prognostic biomarkers in CM. METHODS: We used a CM dataset in The Cancer Genome Atlas (TCGA) to construct FAM molecular subtypes. We performed Kaplan–Meier (K-M) analysis, gene set enrichment analysis (GSEA), and TME analysis to assess differences in the prognosis and immune phenotype between subtypes. We used weighted gene co-expression network analysis (WGCNA) to identify key biomarkers that regulate tumor metabolism and immunity between the subtypes. We compared overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS) between CM patients with high or low biomarker expression. We applied univariable and multivariable Cox analyses to verify the independent prognostic value of the FAM biomarkers. We used GSEA and TME analysis to investigate the immune-related regulation mechanism of the FAM subtype biomarker. We evaluated the immune checkpoint inhibition (ICI) response and chemotherapy sensitivity between CM patients with high or low biomarker expression. We performed real-time fluorescent quantitative PCR (qRT-PCR) and semi-quantitative analysis of the immunohistochemical (IHC) data from the Human Protein Atlas to evaluate the mRNA and protein expression levels of the FAM biomarkers in CM. RESULTS: We identified 2 FAM molecular subtypes (cluster 1 and cluster 2). K-M analysis showed that cluster 2 had better OS and PFS than cluster 1 did. GSEA showed that, compared with cluster 1, cluster 2 had significantly upregulated immune response pathways. The TME analysis indicated that immune cell subpopulations and immune functions were highly enriched in cluster 2 as compared with cluster 1. WGCNA identified 6 hub genes (ACSL5, ALOX5AP, CD1D, CD74, IL4I1, and TBXAS1) as FAM biomarkers. CM patients with high expression levels of the six biomarkers had better OS, PFS, and DSS than those with low expression levels of the biomarkers. The Cox regression analyses verified that the 6 FAM biomarkers can be independent prognostic factors for CM patients. The single-gene GSEA showed that the high expression levels of the 6 genes were mainly enriched in T-cell antigen presentation, the PD-1 signaling pathway, and tumor escape. The TME analysis confirmed that the FAM subtype biomarkers were not only related to immune infiltration but also highly correlated with immune checkpoints such as PD-1, PD-L1, and CTLA-4. TIDE scores confirmed that patients with high expression levels of the 6 biomarkers had worse immunotherapy responses. The 6 genes conveyed significant sensitivity to some chemotherapy drugs. qRT-PCR and IHC analyses verified the expression levels of the 6 biomarkers in CM cells. CONCLUSION: Our FAM subtypes verify that different FAM reprogramming affects the function and phenotype of infiltrating immune cells in the CM TME. The FAM molecular subtype biomarkers can be independent predictors of prognosis and immunotherapy response in CM patients. Frontiers Media S.A. 2022-11-18 /pmc/articles/PMC9716430/ /pubmed/36466837 http://dx.doi.org/10.3389/fimmu.2022.967277 Text en Copyright © 2022 Xu, Chen, Jiang, Yin, Chen, Chi, Wang, Zhang, Zhang and Han 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 Immunology
Xu, Yujian
Chen, Youbai
Jiang, Weiqian
Yin, Xiangye
Chen, Dongsheng
Chi, Yuan
Wang, Yuting
Zhang, Julei
Zhang, Qixu
Han, Yan
Identification of fatty acid metabolism–related molecular subtype biomarkers and their correlation with immune checkpoints in cutaneous melanoma
title Identification of fatty acid metabolism–related molecular subtype biomarkers and their correlation with immune checkpoints in cutaneous melanoma
title_full Identification of fatty acid metabolism–related molecular subtype biomarkers and their correlation with immune checkpoints in cutaneous melanoma
title_fullStr Identification of fatty acid metabolism–related molecular subtype biomarkers and their correlation with immune checkpoints in cutaneous melanoma
title_full_unstemmed Identification of fatty acid metabolism–related molecular subtype biomarkers and their correlation with immune checkpoints in cutaneous melanoma
title_short Identification of fatty acid metabolism–related molecular subtype biomarkers and their correlation with immune checkpoints in cutaneous melanoma
title_sort identification of fatty acid metabolism–related molecular subtype biomarkers and their correlation with immune checkpoints in cutaneous melanoma
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9716430/
https://www.ncbi.nlm.nih.gov/pubmed/36466837
http://dx.doi.org/10.3389/fimmu.2022.967277
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