Identification of a Gene Signature Closely Related to Immunosuppressive Tumour Microenvironment Predicting Prognosis of Patients in EGFR Mutant Lung Adenocarcinoma.

Jia Li,Haiyong Wang,Huahua Li,Chenxing Zhang,Chenyue Zhang,Lifeng Jiang,Huaimin Liu

doi:10.3389/fonc.2021.732841

Abstract

Lung adenocarcinomas (LUADs) harbouring epidermal growth factor receptor (EGFR) mutations are generally unable to benefit from immune checkpoint inhibitors (ICIs) due to an immunosuppressive tumour microenvironment (TME) and a lower tumour mutation burden. Currently, no gene signature can comprehensively evaluate the TME and predict the prognosis of patients with EGFR-mutant LUAD. Using the Cancer Genome Atlas database of EGFR-mutant LUAD based on the immune score derived from the ESTIMATE algorithm, we divided 80 patients with EGFR-mutant LUAD samples into high and low immune score groups with different immune microenvironments. Subsequently, we screened 396 differentially expressed immune-related genes with prognostic value. The top Gene Ontology terms were significantly enriched in biological functions related to T cell differentiation, immune response, cell cycle, and cell proliferation, which are closely related to the immune microenvironment of tumours. In addition, the KEGG pathway enrichment analysis mainly focused on cell cycle, cell adhesion molecules, and cytokine-cytokine receptor interaction, which also had a relationship with the immune response. Subsequently, we identified a three-gene signature including BTLA, BUB1B, and CENPE using the LASSO Cox regression model. The three-gene signature could accurately identify patients at risk of EGFR-mutant LUAD in the training and validation sets and high-risk patients from both the sets exhibited significantly shorter overall survival (p=0.0053 and p=0.035, respectively). CIBERSORT was used to evaluate the abundance of immune cell infiltration in the EGFR-mutant LUAD microenvironment. The immune activity of B cells and macrophages was higher in the low-risk group, while the immune activity of natural killer cells and T cells was higher in the high-risk group. Thus, the three-gene signature closely related to immunosuppressive TME could predict the risk and prognosis in patients with EGFR-mutant LUAD.

Highlights

Lung adenocarcinoma (LUAD) is one of the most common pathological types of non-small cell lung cancer (NSCLC), accounting for approximately half of all lung cancer cases [1]
Epidermal growth factor receptor (EGFR) mutation and mRNA expression profiling data of 108 patients with LUAD were downloaded from the Genomic Data Commons (GDC) repository
The tumour mutation burden (TMB) data of LUAD patients were obtained from the the Cancer Genome Atlas (TCGA) pan-cancer study

Summary

Introduction

Lung adenocarcinoma (LUAD) is one of the most common pathological types of non-small cell lung cancer (NSCLC), accounting for approximately half of all lung cancer cases [1]. Epidermal growth factor receptor (EGFR) mutations are present in approximately 15% of the LUAD cases in Western populations and in approximately 50% of the cases in Asian populations [2, 3]. Patients with EGFR-mutant LUAD showed a significant benefit in terms of progression-free survival with reduced side effects following treatment with tyrosine kinase inhibitors (TKIs). TKIs have shown favourable clinical efficacy in advanced LUAD patients with sensitising EGFR mutations, these patients eventually develop therapeutic resistance [4,5,6]. Immunotherapy with immune-checkpoint inhibitors (ICIs) has achieved impressive success and anti-programmed cell death-1 (PD-1)/anti-programmed cell death ligand-1 (PDL1) inhibitors have been approved by the United States Food and Drug Administration for the treatment of advanced NSCLC. Patients with EGFR-mutant NSCLC rarely derive a significant benefit from ICI therapy [7, 8]

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