Clinical Significance and Immunologic Landscape of a Five-IL(R)-Based Signature in Lung Adenocarcinoma

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.