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BackgroundHigh densities of tertiary lymphoid structures (TLSs) are associated with improved clinical outcomes in various malignancies, including human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). However, the role of TLSs in shaping antitumor immunity in HPV-induced cervical cancer (CESC) remains unclear. Therefore, we analyzed the density, composition, and prognostic impact of TLSs in patients with CESC as well as patients with HNSCC.MethodsMultiplex immunofluorescence, immunohistochemistry, and spatial transcriptomics were used to analyze TLS density and composition in HNSCC and CESC tissue sections with respect to patient prognosis. The spatial approach was supplemented by flow cytometry-based analysis of the polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) phenotype in freshly resected primary tumor tissues.ResultsAlthough both indications were associated with HPV infection, we confirmed a positive correlation between TLS density and improved overall survival only in patients with HNSCC. The TLS composition differed markedly between HNSCC and CESC samples, with a shift toward high regulatory T cell (Treg) and PMN-MDSC abundance in CESC samples. The highest Treg and PMN-MDSC levels were observed in patients with CESC who died of the disease. CESC-infiltrating PMN-MDSCs showed high arginase 1 expression, which correlated with diminished T-cell receptor (TCR)¦Æ chain expression in CESC-infiltrating T cells. Additionally, the high number of PMN-MDSCs in TLSs was associated with the absence of HPV-specific T cells in CESC.ConclusionsUnlike in HNSCC, the composition of TLSs, rather than their quantity, was associated with the overall survival of patients with CESC. High numbers of Tregs and PMN-MDSCs infiltrating immature TLSs prevail in patients with CESC who succumbed to the disease and seem to affect tumor-specific immune responses.

Hermansky-Pudlak Syndrome (HPS) type 1 (HPS-1) is an autosomal recessive disorder characterized by oculocutaneous albinism, platelet dysfunction, and pulmonary fibrosis (HPS-PF), the leading cause of mortality in these patients. HPS-PF manifests earlier than idiopathic pulmonary fibrosis, typically between 30 and 40 years of age. The etiology and drivers of HPS-PF progression remain poorly understood, and no FDA-approved therapies exist. Neutrophil extracellular traps (NETs) and neutrophil-derived mediators have emerged as key players in fibrosis, promoting lung injury, inflammation, and fibroblast activation. This study evaluates the role of neutrophil activation in age-related changes in patients with HPS-1, focusing on differences in inflammatory markers, neutrophil granules, and NETosis capacity. We observed significantly elevated levels of NETs, neutrophil granule proteins (NE, NGAL, LF), and inflammatory cytokines (IL-8, IL-6) in patients with HPS-1 older than 40 years compared to younger patients and healthy controls. Additionally, fibrosis-related markers (MMP-7 and MMP-8) were significantly higher in older patients. Elevated levels of anandamide (AEA), a circulating marker of HPS-PF, were positively associated with neutrophil granule markers in older patients, suggesting its association with fibrosis. Neutrophils from older patients also demonstrated increased NETosis capacity. These findings suggest that age-related neutrophil activation may contribute to an inflammatory environment that promotes fibrosis progression in HPS-1.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13023-025-03758-5.

BackgroundLevels of the human cationic antimicrobial host defence peptide LL-37 are enhanced in the lungs during neutrophilic airway inflammation. LL-37 drives Th17 differentiation, and Th17 cells produce IL-17A and IL-17F which form the biologically active heterodimer IL-17A/F. While IL-17 is a critical mediator of neutrophilic airway inflammation, LL-37 exhibits contradictory functions; LL-37 can both promote and mitigate neutrophil recruitment depending on the inflammatory milieu. The impact of LL-37 on IL-17-induced responses in the context of airway inflammation remains largely unknown. Therefore, we examined signaling intermediates and downstream responses mediated by the interplay of IL-17A/F and LL-37 in human bronchial epithelial cells (HBEC). As LL-37 can become citrullinated during airway inflammation, we also examined LL-37-mediated downstream responses compared to that with citrullinated LL-37 (citLL-37) in HBEC.ResultsUsing an aptamer-based proteomics approach, we identified proteins that are altered in response to IL-17A/F in HBEC. Proteins enhanced in response to IL-17A/F were primarily neutrophil chemoattractants, including chemokines and proteins associated with neutrophil migration such as lipocalin-2 (LCN-2). We showed that selective depletion of LCN-2 mitigates neutrophil migration, functionally demonstrating LCN-2 as a critical neutrophil chemoattractant. We further demonstrated that LL-37 and citLL-37 selectively suppress IL-17A/F-induced LCN-2 abundance in HBEC. Mechanistic studies revealed that LL-37 and citLL-37 suppresses IL-17?A/F-mediated enhancement of C/EBP¦Â, a transcription factor required for LCN-2 production. In contrast, LL-37 and citLL-37 enhance the abundance of ribonuclease Regnase-1, which is a negative regulator of IL-17 and LCN-2 in HBEC. In an animal model of allergen-challenged airway inflammation with elevated IL-17A/F and neutrophil elastase in the lungs, we demonstrated that CRAMP (mouse orthologue of LL-37) negatively correlates with LCN-2.ConclusionsOverall, our findings showed that LL-37 and citLL-37 can selectively suppress the abundance of IL-17A/F-mediated LCN-2, a protein that is critical for neutrophil migration in HBEC. These results suggest that LL-37, and its modified citrullinated form, have the potential to negatively regulate IL-17-mediated neutrophil migration during airway inflammation. To our knowledge, this is the first study to report that the immunomodulatory function of LL-37 enhances the RNA binding protein Regnase-1, suggesting that a post-transcriptional mechanism of action is mediated by the peptide.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12950-025-00446-w.