Construction and Validation of a Tumor Microenvironment-Based Scoring System to Evaluate Prognosis and Response to Immune Checkpoint Inhibitor Therapy in Lung Adenocarcinoma Patients

Abstract

Background: Lung cancer is among the most dangerous malignant tumors to human health. Lung adenocarcinoma (LUAD) accounts for about 40% of all lung cancers. Accumulating evidence suggests that the tumor microenvironment (TME) is a crucial regulator of carcinogenesis and therapeutic efficacy in LUAD. However, the impact of tumor microenvironment-related signatures (TMERSs) representing the TME characteristics on the prognosis and therapeutic outcome of LUAD patients remains to be further explored. Materials and methods: Gene expression files and clinical information of 1630 LUAD samples and 275 samples with immunotherapy information from different databases such as The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Cancer Research Institute (CRI) iAtlas were downloaded and analyzed. Three hundred tumor microenvironment-related signatures (TMERS) based on a comprehensive collection of marker genes were quantified by single sample gene set enrichment analysis (ssGSEA), and then eight significant signatures were selected to construct the tumor microenvironment-related signature score (TMERSscore) by performing Least Absolute Shrinkage and Selection Operator (LASSO)-Cox analysis. Results: In this study, we constructed a TME-based prognostic stratification model for patients with LUAD and validated it in several external datasets. Furthermore, the TMERSscore was found to be positively correlated with tumor malignancy and a high TMERSscore predicted a poor prognosis. Moreover, the TMERSscore of responders treated with Immune Checkpoint Inhibitor (ICI) therapies was significantly lower than that of non-responders, and the TMERSscore was positively correlated with the tumor immune dysfunction and exclusion (TIDE) score, implying that a low TMERSscore predicts a better response to ICI treatment and may provide independent and incremental predictive value over current biomarkers. Conclusions: Overall, we constructed a TMERSscore that can be used for LUAD patient prognosis stratification as well as ICI therapeutic efficacy evaluation, supportive results from independent external validation sets showed its robustness and effectiveness.