Circulating early myeloid-derived suppressor cells as indicators of tumor-driven myelopoiesis and disease progression in lung cancer

Background: Lung cancer (LC) remains the leading cause of cancer-related mortality worldwide. Despite major therapeutic advances, LC patients still experience poor prognosis. Increasing evidence indicates that tumor-driven hematopoietic remodeling and systemic inflammation actively sustain immune suppression and disease progression. The expansion of immature myeloid populations, particularly myeloid-derived suppressor cells (MDSCs), represents a hallmark of tumor-induced emergency myelopoiesis. However, the composition and developmental hierarchy of circulating MDSC subsets remain unclear. Here, we identify a previously unrecognized subset of circulating early MDSCs (eMDSCs) that mirrors tumor-driven myelopoietic activation and lung cancer progression. Methods: In a prospective discovery cohort including LC patients (n=63) and heavy smokers without cancer (HS, n=52), circulating myeloid subsets were characterized from fresh peripheral blood. Multiparametric flow cytometry enabled comprehensive profiling of peripheral blood mononuclear cells (PBMCs). eMDSCs were defined as CD11b⁺CD33⁺CD15⁻ within the Lineage⁻HLA-DR⁻ compartment. A retrospective validation cohort (LC, n=58; HS, n=58), matched for sex, age, and smoking status, confirmed the findings and explored associations with tumor stage and COPD-related inflammation. FACS-sorted eMDSCs from representative LC and HS samples underwent qPCR analysis for PD-L1 and ARG1 expression. Statistical analyses were performed using the Kruskal-Wallis (KW) and Wilcoxon (WILC) tests. Results: In both discovery and validation cohorts (total n=231), LC patients displayed an increased enrichment of circulating CD11b⁺ myeloid populations (WILC test p-value: non-significant p=0.052, p=0.001), particularly Lin⁻HLA-DR⁻CD33⁺CD11b⁺ MDSCs (WILC test p-value: p<0.0001, p=0.009). Within this population, a distinct immature subset of CD15⁻ early MDSCs was identified (WILC test p-value: p<0.0001, p=0.014) and found to be specifically increased in stage II-III LC, but not further expanded at stage IV (KW test p-value: p=0.015). No association emerged between eMDSC levels and COPD-related inflammation, supporting a tumor-specific expansion. Moreover, NK cell frequencies increased in parallel with eMDSCs, suggesting a functional interplay, as eMDSCs may suppress NK activity (KW test p-value: p=0.002). Consistently, qPCR analysis revealed higher PD-L1 and ARG1 expression in LC-derived eMDSCs compared with HS, indicating their immunoregulatory polarization. Conclusion: Our findings identify circulating early MDSCs as a hallmark of lung cancer-associated emergency myelopoiesis. Their selective expansion in stage II-III disease supports their potential as circulating biomarkers to identify and monitor tumor-driven myelopoietic activation and lung cancer progression.