Identification of tumor microenvironment-based gene prognostic signature with promising predictive value for chemo‐immunotherapy outcomes in lung adenocarcinoma patients

Objectives: The tumor microenvironment (TME) plays a critical role in tumor progression and therapeutic response. We aimed to establish a TME-associated gene signature for lung adenocarcinoma (LUAD) patients. Materials and Methods: We comprehensively analyzed the gene expression data of 513 LUAD patients deriving from The Cancer Genome Atlas (TCGA) database. To estimate the composition of TME, The Estimation of Stromal and Immune cells in malignant tumor tissue using the Expression data (ESTIMATE) algorithm was used. We then utilized protein-protein interaction (PPI) analysis, LASSO, and COX regression to explore the related candidate genes with survival. Eventually, a three-gene signature was constructed for risk stratification. Furthermore, we investigated its predictive value in advanced LUAD patients who received chemotherapy alone or combined with anti-PD-1 inhibitors. Results: We identified three genes, namely CCR2, CD40LG, and CCL21, to construct a TME-associated risk stratification gene signature. This gene signature was independently linked to patients' overall survival (OS) among the TCGA dataset (HR, 1.99; 95% CI 1.36-2.93, p < 0.001) and GEO dataset (HR, 1.62; 95%CI 1.19-2.20, p < 0.001). The addition of anti-PD-1 inhibitor Siltuximab to chemotherapy resulted in significantly longer progression-free survival (PFS) in low-risk patients (HR, 0.33; 95% CI: 0.20 - 0.56, p < 0.001) but not in those with high- risk (HR, 0.56; 95% CI:0.24 - 1.31, p = 0.173). Moreover, in patients who received Sintilimab combined with chemotherapy, PFS was significantly different between the high- and low-risk group (HR,1.958; 95%CI:1.079-3.555, p = 0.024), whereas no significant difference was found in chemotherapy alone treated patients (HR, 1.303; 95%CI: 0.610-2.784, p = 0.492). Conclusions: This study generated a three-gene prognostic signature based on TME-associated core genes in patients with LUAD. This gene signature has good value for prognosis prediction. In addition, this signature correlated with treatment outcomes among patients treated with chemotherapy combined with anti-PD1 therapy.