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Dysregulated NK Cell Activation and Myeloid-Lymphoid Imbalance Underpin COPD Progression: Insights from High-Dimensional Immune Profiling and Smoking-Induced Immune Remodeling

ABSTRACT: Background: Chronic obstructive pulmonary disease (COPD) is a significant global health concern, marked by persistent inflammation and immune dysregulation. Although it is widespread and has substantial clinical implications, the systemic immune mechanisms driving disease progression are not fully understood. Since blood contains a diverse array of immune cells and offers a non-invasive means of assessing immune homeostasis and overall physiological status, investigating immune dysregulation through blood sampling offers considerable value for both basic research and clinical application. This approach can provide novel insights into the pathogenesis of COPD. Methods: This study employed high-dimensional flow cytometry and RNA sequencing to comprehensively characterize peripheral immune cells from a cohort of 69 COPD patients spanning clinical stages 1 to 4, alongside 41 healthy donors as controls. To capture granulocyte populations typically excluded from peripheral blood mononuclear cell analyses, fresh whole blood samples were analyzed directly. Results: Our study revealed a marked shift in the myeloid-lymphoid balance, characterized by elevated neutrophils, eosinophils, and classical monocytes that correlated with disease severity, alongside reduced CD8⁺ T cells and circulating T follicular helper cells. Transcriptional profiling identified oxidative stress pathways, T cell suppression, and aberrant natural killer (NK) cell activation as hallmarks of advanced COPD. Notably, activated Nkp44⁺ NK cells were significantly enriched in severe stages, implicating their role in perpetuating inflammation. Smoking exacerbated immune perturbations, including upregulated complement activation and B cell pathways, though cessation partially restored transcriptional homeostasis. Conclusions: This study underscores the value of peripheral immune profiling in capturing the heterogeneity of COPD. The results reveal systemic immune dysregulation-especially NK cell hyperactivity and point to potential therapeutic avenues aimed at modulating immune responses to slow disease progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306950 | GEO | 2025/11/18

REPOSITORIES: GEO

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Project description:Introduction: Tobacco smoking generates airway inflammation in chronic obstructive pulmonary disease (COPD), and its involvement in the development of lung cancer is still among the leading causes of early death. Therefore, we aimed to have a better understanding of the disbalance in immunoregulation in chronic inflammatory conditions in smoker subjects with stable COPD (stCOPD), exacerbating COPD (exCOPD), or non-small cell lung cancer (NSCLC). Methods: Smoker controls without chronic illness were recruited as controls. Through extensive mapping of single cells, surface receptor quantification was achieved by single-cell mass cytometry (CyTOF) with 29 antibodies. The CyTOF characterized 14 main immune subsets such as CD4+, CD8+, CD4+/CD8+, CD4 −/CD8−, and g/d T cells and other subsets such as CD4+ or CD8+ NKT cells, NK cells, B cells, plasmablasts, monocytes, CD11cdim, mDCs, and pDCs. The CD4+ central memory (CM) T cells (CD4+/CD45RA−/CD45RO+/CD197+) and CD4+ effector memory (EM) T cells (CD4+/CD45RA−/CD45RO+/CD197−) were FACSsorted for RNA-Seq analysis. Plasma samples were assayed by Luminex MAGPIX® for the quantitative measurement of 17 soluble immuno-oncology mediators (BTLA, CD28, CD80, CD27, CD40, CD86, CTLA-4, GITR, GITRL, HVEM, ICOS, LAG-3, PD-1, PD-L1, PD-L2, TIM-3, TLR-2) in the four studied groups. Results: Our focus was on T-cell-dependent differences in COPD and NSCLC, where peripheral CD4+ central memory and CD4+ effector memory cells showed a significant reduction in exCOPD and CD4+ CM showed elevation in NSCLC. The transcriptome analysis delineated a perfect correlation of differentially expressed genes between exacerbating COPD and NSCLCderived peripheral CD4+ CM or CD4+ EM cells. The measurement of 17 immuno-oncology soluble mediators revealed a disease-associated phenotype in the peripheral blood of stCOPD, exCOPD, and NSCLC patients. Discussion: The applied single-cell mass cytometry, the whole transcriptome profiling of peripheral CD4+ memory cells, and the quantification of 17 plasma mediators provided complex data that may contribute to the understanding of the disbalance in immune homeostasis generated or sustained by tobacco smoking in COPD and NSCLC.

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Dysregulated NK Cell Activation and Myeloid-Lymphoid Imbalance Underpin COPD Progression: Insights from High-Dimensional Immune Profiling and Smoking-Induced Immune Remodeling

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