Tertiary lymphoid structure signatures are associated with survival and immunotherapy response in lung adenocarcinoma

The presence of tertiary lymphoid structures (TLSs) has been correlated with improved prognosis and clinical outcomes in response to immunotherapy in certain solid tumors. However, the precise role of TLSs in lung adenocarcinoma (LUAD) remains unclear. Four datasets of LUAD were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The TLSs model was constructed using a multivariate Cox proportional hazards model. GO and KEGG analyses were performed to explore the biological process associated with the TLSs model. The ESTIMATE and CIBERSORT algorithms were employed to quantify immune infiltration status. TLSs signature genes (TSGs) were identified, including chemokine signature genes, TFH cell markers, TH1 cell and B cell markers, and a plasma cell marker. Diagnostic evaluations identified key genes with high diagnostic value, particularly among chemokine signature genes and TFH cells markers. Furthermore, high expression of CCL20 and IL1R2 was correlated with poorer outcomes, while other TSGs indicated more favorable prognoses. A novel TLSs score model was constructed, integrating 4 TSGs (SGPP2, MS4A1, IL1R2 and CCL20), which accurately predicted patient survival and was independently associated with prognosis. Additionally, the TLSs score served as a robust indicator for LUAD survival prediction, outperforming traditional staging systems. Comprehensive analyses of enriched pathways and immune cell infiltration patterns revealed that this score involved in metabolic processes and immune cell regulation. Furthermore, the TLSs score showed potential as an indicator of response to immunotherapy, with higher scores associated with reduced expression of immune checkpoint genes and poorer response rates. The TLSs score may serve as a predictor of prognosis and immunotherapeutic response in LUAD. These findings may offer new insights on the study of malignancy and personalized immunotherapy for LUAD patients.