Comprehensive Profiling Reveals Distinct Microenvironment and Metabolism Characterization of Lung Adenocarcinoma.

Chang Li,Yuting Liu,Feifei Gu,Yue Hu,Jingjing Wu,Kai Zhang,Qifan Yang,Yulan Zeng,Di Wu,Juanjuan Wang,Li Liu,Jinyan Liang,Chen Tian,Yangyang Liu

doi:10.3389/fgene.2021.619821

Abstract

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.

Highlights

MATERIALS AND METHODSLung adenocarcinoma is one of the most frequent cause of cancer-related death with a low 5-year survival rate (Hirsch et al, 2017; Bray et al, 2018)
Identification of Lung Adenocarcinoma Immune Subtypes Based on Immune-Related Genes
Lung adenocarcinoma is characterized by the high rate of invasion and metastasis (Bray et al, 2018)

Summary

Introduction

Lung adenocarcinoma is one of the most frequent cause of cancer-related death with a low 5-year survival rate (Hirsch et al, 2017; Bray et al, 2018). High rate of invasion and metastasis are major problems in lung adenocarcinoma. Great advancements in the treatment of lung adenocarcinoma have been achieved in the past few decades. Especially immune checkpoint blockage treatment, has become an emerging paradigm in cancer treatment, which is thought one of the most promising modalities for cancer treatment (Herbst et al, 2018; Saito et al, 2018). The efficacy of ICIs (immune checkpoint inhibitors) varies widely between individuals (Zaretsky et al, 2016), and the survival rate of lung adenocarcinoma remains low. Metabolic reprogramming is an important characteristic of lung adenocarcinoma, which can result in tumor immune evasion and immunosuppression (Li X. et al, 2019). More research into immune escape mechanism and potential therapeutic targets is required to improve the therapeutic effect of immunotherapy and to expand the benefits to a larger population (Mascaux et al, 2019)

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