COPD phenotypes show distinct blood immune signatures linked to lung cancer

Chronic obstructive pulmonary disease does not present a single immune picture in the blood. A cross-sectional study published in Cancer Immunology, Immunotherapy mapped circulating helper T cell subsets, immunosuppressive populations and antigen-presenting cells across specific COPD phenotypes and concurrent lung cancer status, and found that the emphysematous and non-emphysematous forms of the disease carry clearly different systemic immune profiles.

The research team enrolled 64 subjects, 16 in each of four groups: patients with COPD without emphysema, patients with COPD with emphysema, patients with COPD with emphysema and lung cancer, and healthy smoker controls. COPD and emphysema are established independent risk factors for lung cancer, and the study was designed to test whether shared systemic immune alterations might help explain that link. Peripheral blood was analyzed by flow cytometry to enumerate helper T cell subsets, regulatory T cells, monocytic-myeloid-derived suppressor cells and plasmacytoid dendritic cells. Activation of antigen-presenting cells was assessed through HLA-DR expression measured as mean fluorescence intensity, and plasma cytokines were profiled with Luminex xMAP technology.

The clearest signal emerged around HLA-DR, a surface molecule that reflects the activation state of antigen-presenting cells. Both emphysema-associated cohorts, with and without lung cancer, showed lower HLA-DR expression on monocytes and plasmacytoid dendritic cells than the other groups, and the lowest values of all appeared in the group that also had lung cancer. In practical terms, the immune cells responsible for presenting antigen to T cells circulated in a measurably dampened activation state in emphysema, and the addition of cancer deepened that dampening.

The non-emphysematous phenotype told a different story. Patients with COPD but no emphysema showed significantly higher frequencies of regulatory T cells, the monocytic-myeloid-derived suppressor cell phenotype, Th17 cells and the CD194-negative CD196-positive helper T cell subset, together with elevated plasma levels of the cytokine IL-13. Regulatory T cells and myeloid-derived suppressor cells are both recognized as immunosuppressive populations, so this pattern points toward an expanded suppressive arm of the immune system in the non-emphysematous form of the disease rather than a blunted activation state in antigen-presenting cells.

To move beyond single-marker comparisons, the researchers applied linear discriminant analysis and random forest models as exploratory tools for feature prioritization. In these multivariate analyses, plasmacytoid dendritic cell frequency, monocytic-myeloid-derived suppressor cell percentages and the HLA-DR profiles emerged as the primary mathematical features contributing to group characterization. The authors describe these analyses as exploratory, meaning the models highlight which measured variables carry the most weight in separating the groups rather than establishing validated diagnostic rules.

The study’s conclusion is that COPD phenotypes exhibit significant systemic immunological heterogeneity. The non-emphysematous phenotype is associated with expansion of circulating regulatory T cells and an M-MDSC-like subset, while emphysema is characterized by down-regulated HLA-DR expression on circulating antigen-presenting cells, reflecting an altered activation state. Because the two phenotypes diverge so sharply, the authors argue that assessing the clinical phenotype is essential for accurately understanding immune variations in COPD and lung cancer.

Several design features frame how far the findings reach. The study is cross-sectional, capturing immune measurements at a single time point, so it documents associations between phenotype and immune profile rather than demonstrating that one produces the other. The groups were small, with 16 subjects each, and all comparisons were made against healthy smoker controls as well as across disease groups. The lung cancer signal was examined only in combination with emphysema, since the cancer cohort was defined as COPD with emphysema and lung cancer, leaving the immune profile of lung cancer with non-emphysematous COPD outside this dataset.

What the work adds is a phenotype-aware framework for a question that has usually been asked about COPD as a whole. Lung cancer risk is elevated in COPD and in emphysema independently, and shared immune alterations have long been suspected as a connecting mechanism. By showing that the direction of immune change differs between emphysema and non-emphysema phenotypes, the study suggests that pooling COPD patients regardless of phenotype could blur or cancel out immune signals that are real at the phenotype level.

For immunology, the two signatures are mechanistically informative. Down-regulated HLA-DR on monocytes and plasmacytoid dendritic cells in emphysema indicates reduced antigen-presentation capacity in circulation, a state that was most pronounced when lung cancer was present. Expansion of regulatory T cells and monocytic-myeloid-derived suppressor cells alongside Th17 skewing and raised IL-13 in the non-emphysematous phenotype indicates a distinct immunosuppressive and inflammatory composition. Whether either profile predicts future cancer development, treatment response or disease progression cannot be answered by this study, but the measured differences provide a concrete starting point for longitudinal research into how COPD phenotype shapes cancer risk through the immune system.

Subject of Research: Circulating immune cell profiles across COPD phenotypes and concurrent lung cancer

Article Title: Characterization of circulating immune profiles associated with specific COPD phenotypes and concurrent lung cancer status

Article References: Ordóñez, P., Miñana, M. D., Signes-Costa, J., & Soler-Cataluña, J. J. (2026). Characterization of circulating immune profiles associated with specific COPD phenotypes and concurrent lung cancer status. Cancer Immunology, Immunotherapy. https://doi.org/10.1007/s00262-026-04616-4

Image Credits: AI Generated

DOI: 10.1007/s00262-026-04616-4

Keywords: COPD, emphysema, lung cancer, T regulatory cells, myeloid-derived suppressor cells, plasmacytoid dendritic cells, HLA-DR, flow cytometry, Th17 cells, IL-13, immune profiling, cross-sectional study