Pediatric patients with cancer exhibit increased neutrophil extracellular traps and reduced active deoxyribonuclease I: diagnostic, prognostic, and therapeutic opportunities

Abstract

Background Neutrophil extracellular traps (NETs) contribute to cancer progression; however, their value as systemic biomarkers and therapeutic targets in pediatric cancers remains unclear. Purpose To evaluate circulating NET markers as minimally invasive diagnostic and prognostic biomarkers in pediatric cancer and explore the restoration of NET degradation as a therapeutic strategy using recombinant human deoxyribonuclease I (DNaseI). Methods In this prospective cohort study, plasma samples from 182 pediatric patients with diverse tumor types and 10 age-matched healthy controls were analyzed. Circulating NET markers, including cell-free DNA, calprotectin, neutrophil elastase, citrullinated histone H3–DNA complexes, and DNaseI activity, were quantified. NETs were assessed in tumor tissue samples using immunofluorescence. The diagnostic performance and prognostic value were evaluated using receiver operating characteristic and survival analyses, respectively. The ability of patient plasma to degrade NETs and the effects of recombinant human DNaseI supplementation were examined in vitro. Results Plasma cell-free DNA and calprotectin levels were significantly higher in pediatric patients with cancer than in controls, particularly in high-risk patients. Cell-free DNA showed high diagnostic accuracy, whereas calprotectin and DNaseI activity discriminated between high- and low-risk patients and were associated with adverse outcomes. NETs were detected in tumor tissues with heterogeneous distribution and no consistent association with prognosis. Plasma from high-risk patients exhibited impaired NET degradation, which was restored in vitro using recombinant human DNaseI. Conclusion Circulating NETs, especially cell-free DNA and calprotectin, show promise as noninvasive diagnostic and prognostic biomarkers for pediatric cancers. Reduced DNaseI activity identified a potentially targetable mechanism, supporting further investigation of DNaseI-based therapeutic strategies for high-risk pediatric tumors.