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Comprehensive Profiling Reveals Distinct Microenvironment and Metabolism Characterization of Lung Adenocarcinoma

Lung adenocarcinoma has entered into an era of immunotherapy with the development of immune checkpoint inhibitors (ICIs). The identification of immune subtype is crucial to prolonging survival in patients. The tumor microenvironment (TME) and metabolism have a profound impact on prognosis and therap...

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Autores principales: Li, Chang, Tian, Chen, Liu, Yangyang, Liang, Jinyan, Zeng, Yulan, Yang, Qifan, Liu, Yuting, Wu, Di, Wu, Jingjing, Wang, Juanjuan, Zhang, Kai, Gu, Feifei, Hu, Yue, Liu, Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193848/
https://www.ncbi.nlm.nih.gov/pubmed/34122500
http://dx.doi.org/10.3389/fgene.2021.619821
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author Li, Chang
Tian, Chen
Liu, Yangyang
Liang, Jinyan
Zeng, Yulan
Yang, Qifan
Liu, Yuting
Wu, Di
Wu, Jingjing
Wang, Juanjuan
Zhang, Kai
Gu, Feifei
Hu, Yue
Liu, Li
author_facet Li, Chang
Tian, Chen
Liu, Yangyang
Liang, Jinyan
Zeng, Yulan
Yang, Qifan
Liu, Yuting
Wu, Di
Wu, Jingjing
Wang, Juanjuan
Zhang, Kai
Gu, Feifei
Hu, Yue
Liu, Li
author_sort Li, Chang
collection PubMed
description Lung adenocarcinoma has entered into an era of immunotherapy with the development of immune checkpoint inhibitors (ICIs). The identification of immune subtype is crucial to prolonging survival in patients. The tumor microenvironment (TME) and metabolism have a profound impact on prognosis and therapy. The majority of previous studies focused on only one aspect, while both of them are essential to the understanding of tumorigenesis and development. We hypothesized that lung adenocarcinoma can be stratified into immune subgroups with alterations in the TME infiltration. We aimed to explore the “TME-Metabolism-Risk” patterns in each subtypes and the mechanism behind. Glycolysis and cholesterol were selected for the analysis of metabolic states based on the first half of the study. Bioinformatic analysis was performed to investigate the transcriptomic and clinical data integrated by three lung adenocarcinoma cohorts (GSE30219, GSE31210, GSE37745, N = 415). The results were validated in an independent cohort (GSE50081, N = 127). In total, 415 lung adenocarcinoma samples were integrated and analyzed. Four major immune subtypes were indentified using bioinformatic analysis. Subtype NC1, characterized by a high level of glycolysis, with extremely low microenvironment cell infiltration. Subtype NC2, characterized by the “Silence” and “Cholesterol biosynthesis Predominant” metabolic states, with a middle degree infiltration of microenvironment cell. Subtype NC3, characterized by the lack of “Cholesterol biosynthesis Predominant” metabolic state, with abundant microenvironment cell infiltration. Subtype NC4, characterized by “Mixed” metabolic state, with a relatively low microenvironment cell infiltration. Least absolute shrinkage and selection operator (LASSO) regression and multivariate analyses were performed to calculate the risk of each sample, and we attempted to find out the potential immune escape mechanism in different subtypes. The result revealed that the lack of immune cells infiltration might contribute to the immune escape in subtypes NC1 and NC4. NC3 was characterized by the high expression of immune checkpoint molecules and fibroblasts. NC2 had defects in activation of innate immune cells. There existed an obviously survival advantage in subtype NC2. Gene set enrichment analysis (GSEA) and Gene Ontology analysis indicated that the PI3K-AKT-mTOR, TGF-β, MYC-related pathways might be correlated with this phenomenon. In addition, some differentially expressed genes (DEGs) were indentified in subtype NC3, which might be potential targets for survival phenotype transformation.
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spelling pubmed-81938482021-06-12 Comprehensive Profiling Reveals Distinct Microenvironment and Metabolism Characterization of Lung Adenocarcinoma Li, Chang Tian, Chen Liu, Yangyang Liang, Jinyan Zeng, Yulan Yang, Qifan Liu, Yuting Wu, Di Wu, Jingjing Wang, Juanjuan Zhang, Kai Gu, Feifei Hu, Yue Liu, Li Front Genet Genetics Lung adenocarcinoma has entered into an era of immunotherapy with the development of immune checkpoint inhibitors (ICIs). The identification of immune subtype is crucial to prolonging survival in patients. The tumor microenvironment (TME) and metabolism have a profound impact on prognosis and therapy. The majority of previous studies focused on only one aspect, while both of them are essential to the understanding of tumorigenesis and development. We hypothesized that lung adenocarcinoma can be stratified into immune subgroups with alterations in the TME infiltration. We aimed to explore the “TME-Metabolism-Risk” patterns in each subtypes and the mechanism behind. Glycolysis and cholesterol were selected for the analysis of metabolic states based on the first half of the study. Bioinformatic analysis was performed to investigate the transcriptomic and clinical data integrated by three lung adenocarcinoma cohorts (GSE30219, GSE31210, GSE37745, N = 415). The results were validated in an independent cohort (GSE50081, N = 127). In total, 415 lung adenocarcinoma samples were integrated and analyzed. Four major immune subtypes were indentified using bioinformatic analysis. Subtype NC1, characterized by a high level of glycolysis, with extremely low microenvironment cell infiltration. Subtype NC2, characterized by the “Silence” and “Cholesterol biosynthesis Predominant” metabolic states, with a middle degree infiltration of microenvironment cell. Subtype NC3, characterized by the lack of “Cholesterol biosynthesis Predominant” metabolic state, with abundant microenvironment cell infiltration. Subtype NC4, characterized by “Mixed” metabolic state, with a relatively low microenvironment cell infiltration. Least absolute shrinkage and selection operator (LASSO) regression and multivariate analyses were performed to calculate the risk of each sample, and we attempted to find out the potential immune escape mechanism in different subtypes. The result revealed that the lack of immune cells infiltration might contribute to the immune escape in subtypes NC1 and NC4. NC3 was characterized by the high expression of immune checkpoint molecules and fibroblasts. NC2 had defects in activation of innate immune cells. There existed an obviously survival advantage in subtype NC2. Gene set enrichment analysis (GSEA) and Gene Ontology analysis indicated that the PI3K-AKT-mTOR, TGF-β, MYC-related pathways might be correlated with this phenomenon. In addition, some differentially expressed genes (DEGs) were indentified in subtype NC3, which might be potential targets for survival phenotype transformation. Frontiers Media S.A. 2021-05-28 /pmc/articles/PMC8193848/ /pubmed/34122500 http://dx.doi.org/10.3389/fgene.2021.619821 Text en Copyright © 2021 Li, Tian, Liu, Liang, Zeng, Yang, Liu, Wu, Wu, Wang, Zhang, Gu, Hu and Liu. 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
Li, Chang
Tian, Chen
Liu, Yangyang
Liang, Jinyan
Zeng, Yulan
Yang, Qifan
Liu, Yuting
Wu, Di
Wu, Jingjing
Wang, Juanjuan
Zhang, Kai
Gu, Feifei
Hu, Yue
Liu, Li
Comprehensive Profiling Reveals Distinct Microenvironment and Metabolism Characterization of Lung Adenocarcinoma
title Comprehensive Profiling Reveals Distinct Microenvironment and Metabolism Characterization of Lung Adenocarcinoma
title_full Comprehensive Profiling Reveals Distinct Microenvironment and Metabolism Characterization of Lung Adenocarcinoma
title_fullStr Comprehensive Profiling Reveals Distinct Microenvironment and Metabolism Characterization of Lung Adenocarcinoma
title_full_unstemmed Comprehensive Profiling Reveals Distinct Microenvironment and Metabolism Characterization of Lung Adenocarcinoma
title_short Comprehensive Profiling Reveals Distinct Microenvironment and Metabolism Characterization of Lung Adenocarcinoma
title_sort comprehensive profiling reveals distinct microenvironment and metabolism characterization of lung adenocarcinoma
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193848/
https://www.ncbi.nlm.nih.gov/pubmed/34122500
http://dx.doi.org/10.3389/fgene.2021.619821
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