Sitong Chen, Chunyan Li, Yuezhang Sun, Yanyan Huang, Guifu Gong, Yuxuan Bao, Liyun Xu
We identified a distinct population of CD169high large macrophages that is enriched in lung adenocarcinoma-associated MPE and exhibits an immunosuppressive phenotype. CXCL2/CXCR2 axis promotes macrophage migration and contributes to the accumulation of CD169high macrophages in the MPE microenvironment, thereby facilitating MPE progression. These findings provide new insights into the myeloid-cell regulatory mechanisms underlying MPE and may represent a potential therapeutic strategy for lung cancer-associated MPE.
BACKGROUND: Malignant pleural effusion (MPE) correlates with poor prognosis. Tumor-associated macrophages dominate the immune microenvironment and govern MPE progression, while the functional heterogeneity of macrophage subsets in MPE remains poorly understood. CD169+ macrophages exhibit context-dependent tumor-regulatory functions in various malignancies, yet their phenotypic characteristics and biological roles in MPE remain uncharacterized.
METHODS: CD169⁺ macrophages and their CD169low small and CD169high large subsets were characterized in PPE, IPE, and lung adenocarcinoma-associated MPE, as well as in a murine MPE model, by flow cytometry. Their associations with MPE control were analyzed. The effects of CXCL2/CXCR2 signaling on macrophage migration, proliferation, and apoptosis were evaluated using recombinant human CXCL2 and the CXCR2 inhibitor SB225002 in vitro, and the therapeutic effects of CXCR2 inhibition were assessed in vivo.
RESULTS: CD169⁺ macrophages, including CD169low small and CD169high large macrophages, were significantly enriched in lung adenocarcinoma-associated MPE (P < 0.05). Only CD169high large macrophages were negatively associated with MPE control (P < 0.05) and exhibited an immunosuppressive phenotype. Macrophages were the predominant CXCL2-expressing population in single-cell analysis. CXCL2 promoted macrophage migration, whereas CXCR2 inhibition with SB225002 attenuated this effect without affecting macrophage proliferation or apoptosis. In vivo, SB225002 reduced pleural effusion volume, CD169high macrophage accumulation, and tumor burden.
CONCLUSIONS: We identified a distinct population of CD169high large macrophages that is enriched in lung adenocarcinoma-associated MPE and exhibits an immunosuppressive phenotype. CXCL2/CXCR2 axis promotes macrophage migration and contributes to the accumulation of CD169high macrophages in the MPE microenvironment, thereby facilitating MPE progression. These findings provide new insights into the myeloid-cell regulatory mechanisms underlying MPE and may represent a potential therapeutic strategy for lung cancer-associated MPE.