The predictive value of neutrophil extracellular trap-related risk score in prognosis and tertiary lymphoid structure features of lung adenocarcinoma patients

Abstract

Neutrophil extracellular traps have been increasingly recognized as important modulators of tumor immunity. In this study, we investigated the prognostic significance of neutrophil extracellular trap-related genes expression and their impact on tertiary lymphoid structures in lung adenocarcinoma. Using transcriptomic data from The Cancer Genome Atlas and Gene Expression Omnibus cohorts, we identified 4 neutrophil extracellular trap-associated molecular subtypes and developed a robust 13-gene neutrophil extracellular trap-related prognostic signature via Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression. High-risk patients exhibited significantly worse overall survival, higher Tumor Immune Dysfunction and Exclusion (TIDE) and exclusion scores, and decreased cytotoxic activity and tertiary lymphoid structure signatures. Immunohistochemistry of 68 lung adenocarcinoma specimens further validated that high myeloperoxidase expression (a marker of neutrophil extracellular traps) correlated with lower tertiary lymphoid structure density and reduced tertiary lymphoid structure maturation, as indicated by reduced CD21 and BCL6 expression. Functional enrichment and immune infiltration analyses revealed that neutrophil extracellular trap-high tumors were associated with suppressive immune phenotypes, metabolic reprogramming, and impaired lymphoid chemokine expression (eg CCL19, CXCL13). Our findings suggest that neutrophil extracellular traps not only predict poor prognosis in lung adenocarcinoma but may also impair tertiary lymphoid structure maturation and local antitumor immunity, highlighting their potential as therapeutic targets.

Keywords: lung adenocarcinoma; neutrophil extracellular traps; prognostic signature; tertiary lymphoid structures; tumor immune microenvironment.