Identification of age‐ and immune‐related gene signatures for clinical outcome prediction in lung adenocarcinoma

Abstract

BackgroundThe understanding of the factors causing decreased overall survival (OS) in older patients compared to younger patients in lung adenocarcinoma (LUAD) remains.MethodsGene expression profiles of LUAD were obtained from publicly available databases by Kaplan‐Meier analysis was performed to determine whether age was associated with patient OS. The immune cell composition in the tumor microenvironment (TME) was evaluated using CIBERSORT. The fraction of stromal and immune cells in tumor samples were also using assessed using multiple tools including ESTIMATE, EPIC, and TIMER. Differentially expressed genes (DEGs) from the RNA‐Seq data that were associated with age and immune cell composition were identified using the R package DEGseq. A 22‐gene signature composed of DEGs associated with age and immune cell composition that predicted OS were constructed using Least Absolute Shrinkage and Selection Operator (LASSO).ResultsIn The Cancer Genome Atlas (TCGA)‐LUAD dataset, we found that younger patients (≤70) had a significant better OS compared to older patients (>70). In addition, older patients had significantly higher expression of immune checkpoint proteins including inhibitory T cell receptors and their ligands. Moreover, analyses using multiple bioinformatics tools showed increased immune infiltration, including CD4+ T cells, in older patients compared to younger patients. We identified a panel of genes differentially expressed between patients >70 years compared to those ≤70 years, as well as between patients with high or low immune scores and selected 84 common genes to construct a prognostic gene signature. A risk score calculated based on 22 genes selected by LASSO predicted 1, 3, and 5‐year OS, with an area under the curve (AUC) of 0.72, 0.72, 0.69, receptively, in TCGA‐LUAD dataset and an independent validation dataset available from the European Genome‐phenome Archive (EGA).ConclusionOur results demonstrate that age contributes to OS of LUAD patients atleast in part through its association with immune infiltration in the TME.

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“…Patients with oncogenic driver alterations and less immunogenic tumors derive minimal therapeutic benefit from immunotherapy, both of which we observed here for younger patients with NSCLC, especially younger male patients. Consistent with previous reports, we showed younger patients with NSCLC present with lower TMB and differentially expressed immune-related genes compared to older patients (7,14), and that these observations were not driven by the presence or absence of underlying genomic alterations in key NSCLC driver genes ALK or EGFR. Further, we revealed younger patient tumors had markedly reduced gene expression related to activation of the innate and adaptive immune system, and that this reduction was most evident in male patients.…”

“…At the genomic-level, younger patient tumors have been shown to be enriched for clinically actionable genomic alterations including certain drivermutations in EGFR, ALK, ERBB2, and ROS1 and deficient in MET exon 14 skipping mutations compared to older patient tumors (3,6,7,(9)(10)(11)(12)(13). Younger patients have tumors with lower tumor mutational burden (TMB) suggesting they may have reduced responses to immunotherapy compared to older patients (7,14). Younger patient tumors have also been shown to have differentially expressed immune-related genes compared to older patient tumors (14), although more needs to be done to assess the importance of this finding in NSCLC.…”

“…Younger patients have tumors with lower tumor mutational burden (TMB) suggesting they may have reduced responses to immunotherapy compared to older patients (7,14). Younger patient tumors have also been shown to have differentially expressed immune-related genes compared to older patient tumors (14), although more needs to be done to assess the importance of this finding in NSCLC. It remains unclear whether younger patients have better, or worse prognosis or outcomes compared to older patients as previous studies have shown conflicting results (8,10,11,(15)(16)(17)(18)(19)(20)(21).…”

Identification of Immune-Related Genes and Construction of Metastasis Prediction Model for Non-Small Cell Lung Cancer

“…And immune checkpoint inhibitors (ICIs) have become an effective rst-line treatment for driver gene mutation-negative patients(8). Additionally, the 5-year overall survival (OS) rate of metastatic patients has increased from less than 5% to over 30% treated with TKIs and 20% treated with ICIs (9).…”

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“…At the genomic-level, younger patient tumors have been shown to be enriched for clinically actionable genomic alterations including certain drivermutations in EGFR, ALK, ERBB2, and ROS1 and deficient in MET exon 14 skipping mutations compared to older patient tumors (3,6,7,(9)(10)(11)(12)(13). Younger patients have tumors with lower tumor mutational burden (TMB) suggesting they may have reduced responses to immunotherapy compared to older patients (7,14). Younger patient tumors have also been shown to have differentially expressed immune-related genes compared to older patient tumors (14), although more needs to be done to assess the importance of this finding in NSCLC.…”