Abstract
Interleukins (ILs) and interleukin receptors (ILRs) play important role in the antitumor immune response. However, the expression signature and clinical characteristics of the IL(R) family in lung adenocarcinoma (LUAD) remains unclear. The main purpose of this study was to explore the expression profile of IL(R) family genes and construct an IL(R)-based prognostic signature in LUAD. Five public datasets of 1,312 patients with LUAD were enrolled in this study. Samples from The Cancer Genome Atlas (TCGA) were used as the training set, and samples from the other four cohorts extracted from Gene Expression Omnibus (GEO) database were used as the validation set. Additionally, the profile of IL(R) family signature was explored, and the association between this signature and immunotherapy response was also analyzed. Meanwhile, the prognostic value was compared between this IL(R)-based signature and different immunotherapy markers. A signature based on five identified IL(R)s (IL7R, IL5RA, IL20RB, IL11, IL22RA1) was constructed using the TCGA dataset through univariate/multivariable Cox proportional hazards regression and least absolute shrinkage and selection operator (LASSO) Cox analysis. These cases with LUAD were stratified into high- and low-risk group according to the risk score. This signature showed a strong prognostic ability, which was verified by the five independent cohorts and clinical subtypes. The IL(R)-based models presented unique characteristics in terms of immune cell infiltration and immune inflammation profile in tumor microenvironment (TME). Biological pathway analysis confirmed that high-risk patients showed significant T- and B-cell immunosuppression and rapid tumor cell proliferation. More importantly, we researched the relationship between this IL(R)-based signature and immune checkpoints, tumor mutation burden (TMB), tumor purity and ploidy, and tumor immune dysfunction and exclusion (TIDE) score, which confirmed that this signature gave the best prognostic value. We first provided a robust prognostic IL(R)-based signature, which had the potential as a predictor for immunotherapy response to realize individualized treatment of LUAD.
Highlights
Lung cancer is a major type of cancer and an important cause of cancer-related death in China and worldwide [1]
We proposed the IL(R)-based signature to predict the prognosis of lung adenocarcinoma (LUAD) for the first time, which was the first comprehensive understanding of the prognostic characteristics of IL(R) families and their prognostic effect on immunotherapy
Through immune microenvironment and signal pathway analysis, we found that the strong prognostic ability of this IL(R)-based signature was attributed to unique immune cell infiltration ratio, tumor cell proliferation activity, immune cell activity, and antigen processing and presentation mediated by MHC I and MHC II in different risk groups
Summary
Lung cancer is a major type of cancer and an important cause of cancer-related death in China and worldwide [1]. Lung adenocarcinoma (LUAD) accounts for more than 40% of lung cancers and is a major pathological subtype of lung cancer [2]. It is necessary to find a method that can predict patient survival so that the most appropriate personalized treatment can be tailored to different subgroups of patients with lung cancer. The parameters used in these studies were derived from genome-wide and transcriptome data and did not take into account the biological processes of the patients, which might lead to natural errors. These methods were mathematical models that might not reflect the intrinsic characteristics of the tumor itself
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