Exploring the Role of Neutrophils in Pathogenesis of Lymphangioleiomyomatosis.

BACKGROUND

Lymphangioleiomyomatosis (LAM) is a rare, slowly progressive neoplasm, predominantly affecting women, characterized by the presence of diffuse cystic lung disease. Its pathogenesis is driven by mutations in tuberous sclerosis complex (TSC) genes leading to mechanistic target of rapamycin (mTOR) pathway activation, with mTOR inhibitors licensed to slow disease progression. Emerging evidence implicates neutrophils in LAM pathogenesis through oestrogen signalling pathways.

SUMMARY: Preclinical studies using TSC2 null mouse models demonstrate that oestrogen signalling promotes the expansion of neutrophils from bone marrow and recruitment to tumour sites. Immature myeloid-derived suppressor cells (MDSCs) create an immunosuppressive microenvironment that facilitates LAM tumour growth and metastasis. Neutrophil elastase (NE) is a key mediator, promoting tumour cell growth, migration, and invasion. Tumour burden is reduced in preclinical models on inhibition of NE or depletion of MDSCs. Clinical data validate these mechanisms, with elevation of neutrophil count and neutrophil-lymphocyte ratios (NLRs) correlating with accelerated lung function decline and increased incidence of pneumothorax. Both markers decrease following mTOR inhibitor therapy, suggesting pathway connections.

KEY MESSAGES: The role of neutrophils in LAM pathogenesis appears to be mediated through oestrogen signalling pathways. Neutrophil counts and NLR are potential prognostic biomarkers for clinical practice. Potential neutrophil-directed therapies included NE inhibition and agents targeting oestrogen signalling. Further clinical investigation is warranted to translate these mechanistic insights into clinical practice.