Identification and Validation of the Immune Subtypes of Lung Adenocarcinoma: Implications for Immunotherapy

Song, Yang; Shi, Yan; Fan, Wenna; Zhang, Mengyan; Liu, Wei; Lu, Hui; Cao, Ming; Hao, Chenguang; Chen, Lin; Tian, Fanglin; Zhan, Yuning; Cai, Li; Xing, Ying

doi:10.3389/fcell.2020.00550

Cited by 19 publications

(20 citation statements)

References 47 publications

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“…Here, we separately assessed the sensitivity to common chemotherapy drugs and targeted therapy drugs in different risk groups to guide clinical medication. In recent years, cancer immunotherapy has revolutionized LUAD treatment [ 32 ]. Immunotherapies (PD-1, PD-L1, CTLA-4 inhibitors) have shown long-term remission in NSCLC [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Construction of an immune-related lncRNA signature as a novel prognosis biomarker for LUAD

Chen

Shen²,

et al. 2021

Aging

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The tumor immune microenvironment of lung cancer is associated with prognosis and immunotherapy efficacy. Long noncoding RNAs are identified as prognostic biomarkers associated with immune functions. We constructed a signature comprising differentially expressed immune-related lncRNAs to predict the prognosis of patients with lung adenocarcinoma. We established the immune-related lncRNA signature by pairing immune-related lncRNAs regardless of expression level and lung adenocarcinoma patients were divided into high- and low-risk groups. The prognosis of patients in the two groups was significantly different; The immune-related lncRNA signature could serve as an independent lung adenocarcinoma prognostic indicator. The signature correlated negatively with B cell, CD4+ T cell, M2 macrophage, neutrophil, and monocyte immune infiltration. Patients with low risk scores had a higher abundance of immune cells and stromal cells around the tumor. Gene set enrichment analysis showed that samples from low-risk group were more active in the IgA production in intestinal immune network and the T and B cell receptor signaling pathway. High-risk groups had significant involvement of the cell cycle, DNA replication, adherens junction, actin cytoskeleton regulation, pathways in cancer, and TGF-β signaling pathways. High risk scores correlated significantly negatively with high CTLA-4 and HAVCR2 expression and higher median inhibitory concentration of common anti-tumor chemotherapeutics (e.g., cisplatin, paclitaxel, gemcitabine) and targeted therapy (e.g., erlotinib and gefitinib). We identified a reliable immune-related lncRNA lung adenocarcinoma prognosis model, and the immune-related lncRNA signature showed promising clinical prediction value.

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Section: Discussionmentioning

confidence: 99%

Construction of an immune-related lncRNA signature as a novel prognosis biomarker for LUAD

Chen

Shen²,

et al. 2021

Aging

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“…As an emerging therapeutic approach for malignancies, tumor immunotherapy, particularly for ICB therapy, is increasingly proved to be effective for LUAD patients (Huang et al, 2020a;Kano et al, 2020). However, a remarkable improvement in overall response rate and prognosis for LUAD patients is still not achieved due to the inherent intertumoral and intratumoral heterogeneity and the development of acquired resistance to ICB therapy (Jin et al, 2020;Song et al, 2020). To address this issue, a promising biomarker which is capable of predicting therapeutic efficiency before treatment is needed to screen potential responsive subpopulation prior to treatment and monitor the therapeutic efficiency during the process of treatment (Meyers and Banerji, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…To address this issue, a promising biomarker which is capable of predicting therapeutic efficiency before treatment is needed to screen potential responsive subpopulation prior to treatment and monitor the therapeutic efficiency during the process of treatment (Meyers and Banerji, 2020). Tumor-immune relationship plays an important role in tumor development and tumor progression, and tumor immune microenvironment (TIM) is widely accepted as a significant factor influencing therapeutic efficiency of ICB therapy (Song et al, 2020;Wang et al, 2020). Specifically, tumorinfiltrating lymphocytes (TILs) score (Gascón et al, 2020;Hashemi et al, 2021) and PD-L1 status (Wu et al, 2020) were previously suggested as potential biomarkers to be applied in clinical practice for LUAD.…”

Section: Discussionmentioning

confidence: 99%

“…Owing to heterogeneity existing in LUAD and development of acquired resistance to ICB therapy, the overall performance of ICB therapy in clinical practice for LUAD is far from satisfactory (Pathak et al, 2020). As one of the most immunological cancer type, immunological surveillance, immunoediting and immune escape play a critical role in LUAD development and progression (Song et al, 2020). Screening for potentially responsive LUAD patients to ICB therapy before treatment by using an effective immunoligical biomarker is beneficial to remarkably improve the outcome of LUAD patients with ICB therapy (Wu et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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The Predictive Role of Immune Related Subgroup Classification in Immune Checkpoint Blockade Therapy for Lung Adenocarcinoma

Wang

Chen

et al. 2021

Front. Genet.

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Background: In lung adenocarcinoma (LUAD), the predictive role of immune-related subgroup classification in immune checkpoint blockade (ICB) therapy remains largely incomplete.Methods: Transcriptomics analysis was performed to evaluate the association between immune landscape and ICB therapy in lung adenocarcinoma and the associated underlying mechanism. First, the least absolute shrinkage and selection operator (LASSO) algorithm and K-means algorithm were used to identify immune related subgroups for LUAD cohort from the Cancer Genome Atlas (TCGA) database (n = 572). Second, the immune associated signatures of the identified subgroups were characterized by evaluating the status of immune checkpoint associated genes and the immune cell infiltration. Then, potential responses to ICB therapy based on the aforementioned immune related subgroup classification were evaluated via tumor immune dysfunction and exclusion (TIDE) algorithm analysis, and survival analysis and further Cox proportional hazards regression analysis were also performed for LUAD. In the end, gene set enrichment analysis (GSEA) was performed to explore the metabolic mechanism potentially responsible for immune related subgroup clustering. Additionally, two LUAD cohorts from the Gene Expression Omnibus (GEO) database were used as validation cohort.Results: A total of three immune related subgroups with different immune-associated signatures were identified for LUAD. Among them, subgroup 1 with higher infiltration scores for effector immune cells and immune checkpoint associated genes exhibited a potential response to IBC therapy and a better survival, whereas subgroup 3 with lower scores for immune checkpoint associated genes but higher infiltration scores for suppressive immune cells tended to be insensitive to ICB therapy and have an unfavorable prognosis. GSEA revealed that the status of glucometabolic reprogramming in LUAD was potentially responsible for the immune-related subgroup classification.Conclusion: In summary, immune related subgroup clustering based on distinct immune associated signatures will enable us to screen potentially responsive LUAD patients for ICB therapy before treatment, and the discovery of metabolism associated mechanism is beneficial to comprehensive therapeutic strategies making involving ICB therapy in combination with metabolism intervention for LUAD.

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“…This indicates that there has been a growing recognition of the role of CNVs in tumorigenesis. At present, there are several researches on molecular genotyping identified using immune related transcriptome data in LUAD ( 20 , 21 ). Based on these reports, we attempted to use the DNA copy-number-correlated (CNVcor) genes to conducte molecular subtypes in LUAD.…”

Section: Introductionmentioning

confidence: 99%

Molecular subtypes based on CNVs related gene signatures identify candidate prognostic biomarkers in lung adenocarcinoma

Huang

et al. 2021

Neoplasia

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The classical factors for predicting prognosis currently cannot meet the developing requirements of individualized and accurate prognostic evaluation in lung adenocarcinoma (LUAD). With the rapid development of high-throughput DNA sequencing technologies, genomic changes have been discovered. These sequencing data provide unprecedented opportunities for identifying cancer molecular subtypes. In this article, we classified LUAD into two distinct molecular subtypes (Cluster 1 and Cluster 2) based on Copy Number Variations (CNVs) and mRNA expression data from the Cancer Genome Atlas (TCGA) based on non-negative matrix factorization. Patients in Cluster 1 had worse outcomes than that in Cluster 2. Molecular features in subtypes were assessed to explain this phenomenon by analyzing differential expression genes expression pattern, which involved in cellular processes and environmental information processing. Analysis of immune cell populations suggested different distributions of CD4+ T cells, CD8+ T cells, and dendritic cells in the two subtypes. Subsequently, two novel genes, TROAP and RASGRF1, were discovered to be prognostic biomarkers in TCGA, which were confirmed in GSE31210 and Tianjin Medical University Cancer Institute and Hospital LUAD cohorts. We further proved their crucial roles in cancers by vitro experiments. TROAP mediates tumor cell proliferation, cycle, invasion, and migration, not apoptosis. RASGRF1 has a significant effect on tumor microenvironment. In conclusion, our study provides a novel insight into molecular classification based on CNVs related genes in LUAD, which may contribute to identify new molecular subtypes and target genes.

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Identification and Validation of the Immune Subtypes of Lung Adenocarcinoma: Implications for Immunotherapy

Cited by 19 publications

References 47 publications

Construction of an immune-related lncRNA signature as a novel prognosis biomarker for LUAD

Construction of an immune-related lncRNA signature as a novel prognosis biomarker for LUAD

The Predictive Role of Immune Related Subgroup Classification in Immune Checkpoint Blockade Therapy for Lung Adenocarcinoma

Molecular subtypes based on CNVs related gene signatures identify candidate prognostic biomarkers in lung adenocarcinoma

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