Integration of multiple key molecules in lung adenocarcinoma identifies prognostic and immunotherapeutic relevant gene signatures

Abstract

BackgroundAlthough multiple key molecules in lung adenocarcinoma (LUAD) have been identified in recent years, the overall tumor microenvironment (TME) immune cell infiltration characterizations mediated by multiple key molecules remain little known. This study aimed to integrate the roles of multiple key molecules to evaluate patient prognosis and TME cell infiltration characterization as well as responses to immunotherapy. MethodsUsing combined LUAD cancer cohorts with 228 normal samples and 913 tumor samples, we comprehensively dissected the differences of genomic and TME cell infiltration landscapes between normal lung tissues and tumor tissues. The single-sample gene-set enrichment analysis (ssGSEA) was used to quantify the relative abundance of 24 cell infiltration. The riskScore signature was constructed using a least absolute shrinkage and selection operator (LASSO) Cox regression mode. ResultsSeven novel key molecules with significantly up-regulated expression in LUAD were determined. Survival analyses revealed their important prognostic values. LUAD microenvironment presented a markedly decreased infiltration of immune cells compared to normal lung tissues. We found tumors with up-regulated expression of these key molecules exhibited a significantly decreased TME cell infiltration and increased immune checkpoint molecule expression. The high riskScore subtype was characterized by decreased innate and adaptive immune cell infiltration. Activation of p53 signaling pathway and regulator T cells were observed in the high riskScore subtype, which were regarded as T-cell suppressive and could be responsible for poorer prognosis in this subtype (HR 1.83(1.27–2.63)). Multivariate analyses demonstrated the riskScore was a robust and independent prognostic biomarker, and its value in predicting immunotherapeutic outcomes was also confirmed (HR 1.70(1.22–2.37)). ConclusionsThis study reveal a novel gene signature significantly related to patient prognosis and TME cell infiltration in LUAD. We demonstrated the integrated roles of multiple key molecules played a crucial role in shaping TME cell infiltration diversity and complexity. Evaluating the integrated characterization of multiple key molecules could contribute to predicting patients’ response to immunotherapy and guiding more effective immunotherapy strategies.