Pleural cavity macrophages promote lung tumor establishment through tissue invasion

To investigate their recruitment, Gata6-iCreER mice were crossed with Cd45-Dre and R26-tdT mice, enabling specific lineage tracing of cavity macrophages. Flow cytometry and immunofluorescence confirmed their infiltration into lung tumors, where they constituted for ~50% of tumor-associated macrophages. Similar observations were made in Hepa1-6 and LLC metastasis models, suggesting a broad role across tumor types.

To assess functional relevance, a Gata6-RSR-tdT-DTR mouse model was developed for diphtheria toxin (DT)-mediated macrophage depletion. DT treatment significantly reduced tumor burden and extended survival, confirming their pro-tumor effects. Gata6 knockout in cavity macrophages significantly suppressed metastasis. However, cell depletion after tumor establishment showed limited efficacy, indicating their primary role in early tumor growth.

Mechanistically, macrophage depletion increased cytotoxic CD8⁺ T cells in tumors and pleural cavities, suggesting that cavity macrophages suppress anti-tumor immunity. These findings establish cavity macrophages as key drivers of tumor progression and propose their targeting as a potential therapeutic strategy. Further research is needed to elucidate the molecular mechanisms driving their migration and immunosuppressive functions.