Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA Analysis
Immunotherapy resistance is a major barrier in the application of immune checkpoint inhibitors (ICI) in lung adenocarcinoma (LUAD) patients. Although recent studies have found several mechanisms and potential genes responsible for immunotherapy resistance, ways to solve this problem are still lackin...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-01-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.814014/full |
| _version_ | 1798035646627971072 |
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| author | Weina Yu Weina Yu Weina Yu Fengsen Liu Fengsen Liu Fengsen Liu Qingyang Lei Qingyang Lei Qingyang Lei Peng Wu Peng Wu Peng Wu Li Yang Li Yang Li Yang Yi Zhang Yi Zhang Yi Zhang Yi Zhang |
| author_facet | Weina Yu Weina Yu Weina Yu Fengsen Liu Fengsen Liu Fengsen Liu Qingyang Lei Qingyang Lei Qingyang Lei Peng Wu Peng Wu Peng Wu Li Yang Li Yang Li Yang Yi Zhang Yi Zhang Yi Zhang Yi Zhang |
| author_sort | Weina Yu |
| collection | DOAJ |
| description | Immunotherapy resistance is a major barrier in the application of immune checkpoint inhibitors (ICI) in lung adenocarcinoma (LUAD) patients. Although recent studies have found several mechanisms and potential genes responsible for immunotherapy resistance, ways to solve this problem are still lacking. Tumor immune dysfunction and exclusion (TIDE) algorithm is a newly developed method to calculate potential regulators and indicators of ICI resistance. In this article, we combined TIDE and weighted gene co-expression network analysis (WGCNA) to screen potential modules and hub genes that are highly associated with immunotherapy resistance using the Cancer Genome Atlas (TCGA) dataset of LUAD patients. We identified 45 gene co-expression modules, and the pink module was most correlated with TIDE score and other immunosuppressive features. After considering the potential factors in immunotherapy resistance, we found that the pink module was also highly related to cancer stemness. Further analysis showed enriched immunosuppressive cells in the extracellular matrix (ECM), immunotherapy resistance indicators, and common cancer-related signaling pathways in the pink module. Seven hub genes in the pink module were shown to be significantly upregulated in tumor tissues compared with normal lung tissue, and were related to poor survival of LUAD patients. Among them, THY1 was the gene most associated with TIDE score, a gene highly related to suppressive immune states, and was shown to be strongly expressed in late-stage patients. Immunohistochemistry (IHC) results demonstrated that THY1 level was higher in the progressive disease (PD) group of LUAD patients receiving a PD-1 monoclonal antibody (mAb) and positively correlated with SOX9. Collectively, we identified that THY1 could be a critical biomarker in predicting ICI efficiency and a potential target for avoiding tumor immunotherapy resistance. |
| first_indexed | 2024-04-11T21:01:09Z |
| format | Article |
| id | doaj.art-7ab40b5fda1a421b81fcb452bddd45a8 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-11T21:01:09Z |
| publishDate | 2022-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-7ab40b5fda1a421b81fcb452bddd45a82022-12-22T04:03:29ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-01-011110.3389/fonc.2021.814014814014Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA AnalysisWeina Yu0Weina Yu1Weina Yu2Fengsen Liu3Fengsen Liu4Fengsen Liu5Qingyang Lei6Qingyang Lei7Qingyang Lei8Peng Wu9Peng Wu10Peng Wu11Li Yang12Li Yang13Li Yang14Yi Zhang15Yi Zhang16Yi Zhang17Yi Zhang18Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaHenan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou University, Zhengzhou, ChinaState Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, ChinaBiotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaHenan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou University, Zhengzhou, ChinaState Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, ChinaBiotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaHenan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou University, Zhengzhou, ChinaState Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, ChinaBiotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaHenan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou University, Zhengzhou, ChinaState Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, ChinaBiotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaHenan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou University, Zhengzhou, ChinaState Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, ChinaBiotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaHenan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou University, Zhengzhou, ChinaState Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, ChinaSchool of Life Sciences, Zhengzhou University, Zhengzhou, ChinaImmunotherapy resistance is a major barrier in the application of immune checkpoint inhibitors (ICI) in lung adenocarcinoma (LUAD) patients. Although recent studies have found several mechanisms and potential genes responsible for immunotherapy resistance, ways to solve this problem are still lacking. Tumor immune dysfunction and exclusion (TIDE) algorithm is a newly developed method to calculate potential regulators and indicators of ICI resistance. In this article, we combined TIDE and weighted gene co-expression network analysis (WGCNA) to screen potential modules and hub genes that are highly associated with immunotherapy resistance using the Cancer Genome Atlas (TCGA) dataset of LUAD patients. We identified 45 gene co-expression modules, and the pink module was most correlated with TIDE score and other immunosuppressive features. After considering the potential factors in immunotherapy resistance, we found that the pink module was also highly related to cancer stemness. Further analysis showed enriched immunosuppressive cells in the extracellular matrix (ECM), immunotherapy resistance indicators, and common cancer-related signaling pathways in the pink module. Seven hub genes in the pink module were shown to be significantly upregulated in tumor tissues compared with normal lung tissue, and were related to poor survival of LUAD patients. Among them, THY1 was the gene most associated with TIDE score, a gene highly related to suppressive immune states, and was shown to be strongly expressed in late-stage patients. Immunohistochemistry (IHC) results demonstrated that THY1 level was higher in the progressive disease (PD) group of LUAD patients receiving a PD-1 monoclonal antibody (mAb) and positively correlated with SOX9. Collectively, we identified that THY1 could be a critical biomarker in predicting ICI efficiency and a potential target for avoiding tumor immunotherapy resistance.https://www.frontiersin.org/articles/10.3389/fonc.2021.814014/fullLUADWGCNATIDEimmunotherapy resistancecancer stem cell |
| spellingShingle | Weina Yu Weina Yu Weina Yu Fengsen Liu Fengsen Liu Fengsen Liu Qingyang Lei Qingyang Lei Qingyang Lei Peng Wu Peng Wu Peng Wu Li Yang Li Yang Li Yang Yi Zhang Yi Zhang Yi Zhang Yi Zhang Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA Analysis Frontiers in Oncology LUAD WGCNA TIDE immunotherapy resistance cancer stem cell |
| title | Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA Analysis |
| title_full | Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA Analysis |
| title_fullStr | Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA Analysis |
| title_full_unstemmed | Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA Analysis |
| title_short | Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA Analysis |
| title_sort | identification of key pathways and genes related to immunotherapy resistance of luad based on wgcna analysis |
| topic | LUAD WGCNA TIDE immunotherapy resistance cancer stem cell |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.814014/full |
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