Development of an Immune-Related Risk Signature for Predicting Prognosis in Lung Squamous Cell Carcinoma.

Denggang Fu,Biyu Zhang,Lei Yang,Shaoxin Huang,Wang Xin

doi:10.3389/fgene.2020.00978

Abstract

Lung squamous cell carcinoma (LSCC) is the most common subtype of non-small cell lung cancer. Immunotherapy has become an effective treatment in recent years, while patients showed different responses to the current treatment. It is vital to identify the potential immunogenomic signatures to predict patient’ prognosis. The expression profiles of LSCC patients with the clinical information were downloaded from TCGA database. Differentially expressed immune-related genes (IRGs) were extracted using edgeR algorithm, and functional enrichment analysis showed that these IRGs were primarily enriched in inflammatory- and immune-related processes. “Cytokine-cytokine receptor interaction” and “PI3K-AKT signaling pathway” were the most enriched KEGG pathways. 27 differentially expressed IRGs were significantly correlated with the overall survival (OS) of patients using univariate Cox regression analysis. A prognostic risk signature that comprises seven IRGs (GCCR, FGF8, CLEC4M, PTH, SLC10A2, NPPC, and FGF4) was developed with effective predictive performance by multivariable Cox stepwise regression analysis. Most importantly, the signature could be an independent prognostic predictor after adjusting for clinicopathological parameters, and also validated in two independent LSCC cohorts (GSE4573 and GSE17710). Potential molecular mechanisms and tumor immune landscape of these IRGs were investigated through computational biology. Analysis of tumor infiltrating lymphocytes and immune checkpoint molecules revealed distinct immune landscape in high- and low-risk group. The study was the first time to construct IRG-based immune signature in the recognition of disease progression and prognosis of LSCC patients.

Highlights

Lung cancer is the second most prevalent human malignancy that arises from epithelial cells in both men and women, and is by far the leading cause of cancer death worldwide, accounting for 25% of all cancer deaths
Stage Lung squamous cell carcinoma (LSCC) patients are typically receiving resected surgically and chemotherapy and/or radiation could be as an adjuvant therapy, while advanced LSCC are given the firstline systematic therapy, commonly a platinum-based regimens (Gandara et al, 2015).Compared to lung adenocarcinoma, much less frequent mutations in EGFR and ALK rearrangements for LSCC postponed the development of targeted therapies (Derman et al, 2015; Yang et al, 2019)
Patients with LSCC have benefited from an expanding immunotherapies, such as programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition, VEGFR inhibition, and targeted therapies matched to fibroblast growth factor receptor (FGFR) and PI3KAKT (Derman et al, 2015)

Summary

Introduction

Lung cancer is the second most prevalent human malignancy that arises from epithelial cells in both men and women, and is by far the leading cause of cancer death worldwide, accounting for 25% of all cancer deaths. Stage LSCC patients are typically receiving resected surgically and chemotherapy and/or radiation could be as an adjuvant therapy, while advanced LSCC are given the firstline systematic therapy, commonly a platinum-based regimens (Gandara et al, 2015).Compared to lung adenocarcinoma, much less frequent mutations in EGFR and ALK rearrangements for LSCC postponed the development of targeted therapies (Derman et al, 2015; Yang et al, 2019). As an aggressive disease with leading mortality and incidence worldwide, several databases were constructed to find prognosis related biomarkers in lung cancer, while few online survival analysis softwares available for specific subtypes of lung cancer except than Kaplan-Meier plotter (Gyõrffy et al, 2013) and OSluca (Yan et al, 2020)

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