Single-cell sequencing reveals CXCL14 upregulation and dendritic cell subset imbalance in the immunologic transition from chronic obstructive pulmonary disease to non-small cell lung cancer
ZHEN Li-fang
SHAO Jie
WANG Ya-qin
LI Rui-dan
QIN Ya-hong
WU Shui-miao
Abstract：Objective To elucidate the immunologic mechanisms by which upregulation of chemokine ligand 14(CXCL14)and imbalance of dendritic cell(DC)subsets contribute to the transition from chronic obstructive pulmonary disease(COPD)to non-small cell lung cancer(NSCLC).Methods Clinical participants were recruited into four groups:smoking healthy controls(SmHC),stable COPD(stCOPD),acute exacerbation COPD(exCOPD),and newly diagnosed,treatment-naïve smoking NSCLC(NSCLC),with three subjects in each group.Peripheral venous blood and induced sputum samples were collected.Cytokine profiles in sputum were assessed using antibody microarray chips.Dif-ferential mRNA expression of cytokines was validated by qRT-PCR.Single-cell mass cytometry was applied to profile peripheral blood mononuclear cells(PBMCs),enabling immune-cell quantification,metaclustering,and UMAP-based dimensionality reduction.Flow cytometry validated surface markers of plasmacytoid dendritic cells(pDCs;CD64+DCs),conventional DC1s(cDC1s;CD64+MAR-1+CXCL14+DCs),and conventional DC2s(cDC2s;CD64+CXCL14+DCs),and quantified subset proportions among differentiating DCs in the four study groups.Results Compared with the stCOPD group,the NSCLC sputum samples demonstrated significant upregulation of interleukin 6(IL-6),programmed death ligand 1(PD-L1),CD86,Toll-like receptor 2(TLR-2),programmed death 1(PD-1),lymphocyte activa-tion gene 3(LAG-3),interleukin-1α(IL-1α),bone morphogenetic protein 4(BMP-4),transforming growth fac-tor-β1(TGF-β1),CXCL14,and macrophage colony-stimulating factor receptor(M-CSF)(P＜0.01),as well as cytotoxic T-lymphocyte-associated antigen 4(CTLA-4)and T cell immunoglobulin and mucin-domain-containing-3(TIM-3)(P＜0.05).Bone morphogenetic protein 6(BMP-6)and monokine induced by interferon-γ(MIG)were significantly downregulated(P＜0.01).CXCL14 mRNA levels were elevated in NSCLC compared with exCOPD(P＜0.05).Single-cell mass cytometry identified 12 major immune-cell metaclusters,including pDCs(3.92％),cDC1s(3.85％),and cDC2s(2.63％).PD-1 and PD-L1 exhibited varying degrees of upregulation across these DC sub-sets.Compared with stCOPD,the proportions of cDC1s and cDC2s increased in exCOPD and NSCLC(P＜0.05).Com-pared with exCOPD,NSCLC patients showed higher expression of MAR-1 and CXCL14 in cDC1s(P＜0.05),increased CXCL14 expression in cDC2s(P＜0.05),and elevated CD64 expression in cDC1s,cDC2s,and pDCs(P＜0.05).Proportions of cDC1s and cDC2s were also significantly increased(P＜0.05).Conclusion CXCL14 upregulation and imbalance of DC subsets,particularly cDC1 and cDC2 expansion accompanied by immunoregulatory marker elevation,may play critical roles in driving the immunologic shift from COPD to NSCLC.
Keywords：chronic obstructive pulmonary diseasenon-small cell lung cancersingle-cell sequencingden-dritic cellsCXCL14 chemokine
Publication Date：2026-01-15
Online Publishing Date：2026-03-04(First online date of this platform, not the publication date of the document)
Pages：10( 45-54 )