8068 Background: Immune aging has been associated with survival outcomes in patients with lung adenocarcinoma (LUAD), but its relevance within the tumor microenvironment (TME) remains unclear. Methods: Clinical and RNA-sequencing data from the TCGA LUAD cohort were analyzed. Immune aging within tumor tissue was quantified using a predefined 121-gene immune aging–related signature (IAS-121). For primary analyses, patients were dichotomized into high versus low IAS-121 groups based on the median value. Immune cell composition within the TME was inferred using xCell analysis and compared according to IAS-121 status. Overall survival (OS) was assessed using Kaplan–Meier analysis and Cox proportional hazards models adjusted for age, sex, tumor stage, smoking status, and EGFR mutation status. Sensitivity analyses were performed using quartile-based categorization of IAS-121 (lowest vs highest quartile), and external validation was conducted in two independent LUAD cohorts (GSE68465 and GSE50081). Results: A total of 518 patients with LUAD from the TCGA cohort were included. Patients with high IAS-121 had significantly poorer OS compared with those with low IAS-121 (p=0.026). In multivariable analysis using the median cut-off, high IAS-121 showed a non-significant trend toward increased mortality (adjusted hazard ratio aHR 1.33; 95% confidence interval CI, 0.96–1.84). In sensitivity analyses comparing the lowest and highest quartiles of IAS-121, a significant association with OS was observed (aHR 1.87; 95% CI, 1.20–2.92). This association was further confirmed in a pooled analysis of the external LUAD cohorts (GSE68465 and GSE50081), in which higher IAS-121 was independently associated with worse OS (aHR 1.57; 95% CI, 1.02–2.43). Subgroup analyses showed generally consistent associations across age, sex, tumor stage, smoking status, and EGFR mutation status. Tumors with high IAS-121 exhibited reduced enrichment of CD8⁺ T cells and CD4⁺ naïve T cells, along with increased neutrophil enrichment. Conclusions: Immune aging within TME is associated with poorer survival in LUAD. As this study is hypothesis-generating, further investigations integrating tissue- and blood-based measures of immune aging are warranted to clarify its clinical and biological implications. Cox proportional hazards models comparing the lowest versus highest quartile of immune aging score-121 and overall survival in lung adenocarcinoma. TCGA GSE68465 plus GSE50081 HR (95% CI) p HR (95% CI) p Crude 1.648 (1.114 – 2.238) 0.012 2.093 (1.396 – 3.141) <0.001 Adjusted 1.873 (1.200 – 2.924) 0.006 1.571 (1.016 – 2.429) 0.007 Models adjusted age, sex, tumor stage, smoking status, and EGFR mutation status for TCGA dataset and age, sex, tumor stage for GSE68465 plus GSE50081 cohorts. LUAD = lung adenocarcinoma; HR = hazard ratio; CI = confidence level.
Kim et al. (Thu,) studied this question.