Work

Integrating proteomics to map immune landscape and protein biomarkers for risk stratification in childhood Langerhans cell histiocytosis

Year: 2026

Type: article

Abstract: Background: Langerhans cell histiocytosis (LCH) is a rare pediatric disease with marked clinical heterogeneity. Current risk stratification relies on the extent of organ involvement and risk-organ status, yet reliable protein biomarkers for distinguishing LCH subtypes are lacking. Methods: We performed proteomic analysis on 56 formalin-fixed paraffin-embedded (FFPE) pediatric LCH tissue samples and 10 normal skin controls, quantifying 6, 914 proteins. Machine-learning approaches were integrated with weighted correlation network analysis for exploratory identification of candidate protein biomarkers and internal classification analysis. Candidate markers were validated by immunohistochemistry. The CIBERSORT deconvolution algorithm was employed to estimate the immune cell infiltration. Results: Proteomic profiling clearly distinguished LCH from controls. Functional protein modules and candidate protein biomarkers were identified across different LCH subtypes. Significant differences in immune cell infiltration were also observed, revealing enhanced innate immune activation and cytotoxic T cell responses in multisystem LCH compared with single-system LCH, as well as in LCH with risk-organ involvement versus those without. In exploratory internal classification analyses, the SVM model yielded an accuracy, AUC, and F1 score of 1.000 (95% CI: 1.000-1.000) for distinguishing multisystem from single-system LCH. For risk-organ involvement, the KNN model yielded an accuracy of 0.800 (95% CI: 0.500-1.000) and an AUC of 0.880 (95% CI: 0.600-1.000). Conclusion: To our knowledge, this is the first large-scale FFPE-based proteomic study in pediatric LCH to reveal subtype and risk specific protein signatures and associated immune cell profiles changes. These findings provide novel biological insights into LCH heterogeneity and identify candidate protein biomarkers associated with disease extent and risk-organ involvement. Further validation in larger independent cohorts is required before their predictive or clinical utility can be established.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1909960