Myeloid cell-derived PROS1 inhibits tumor metastasis by regulating inflammatory and immune responses via IL-10

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• TAM receptor tyrosine kinases (TYRO3, AXL, MERTK) are implicated in tumor progression.
• TAM ligands GAS6 and PROS1 are secreted by immune cells, potentially aiding tumor growth.

Purpose of the Study:

• To investigate the role of myeloid-derived PROS1 in cancer metastasis.
• To elucidate the mechanisms by which PROS1 influences tumor cell behavior and immune responses.

Main Methods:

• Utilized myeloid-specific Pros1 conditional knockout (cKO) mouse models in lung and breast cancer settings.
• Analyzed gene and protein expression in bone marrow-derived macrophages (BMDMs) and tumor cells.
• Assessed immune cell function, including T cell proliferation and dendritic cell (DC) costimulatory molecule expression.
• Investigated the role of MERTK kinase activity.

Main Results:

• Myeloid Pros1 deletion significantly increased lung metastasis, independent of primary tumor infiltration.
• cKO BMDMs exhibited elevated TNF-α, IL-6, Nos2, and IL-10 via Socs3/NF-κB pathway modulation.
• Conditioned medium from cKO BMDMs promoted tumor cell epithelial-mesenchymal transition (EMT), enhanced ERK, AKT, and STAT3 signaling, and supported IL-10-dependent invasion and survival.
• PROS1-dependent modulation of T cell and DC function was observed in metastatic lungs.
• MERTK inhibition partially blocked PROS1's effect on TNF-α and IL-6 but not IL-10.

Conclusions:

• Identified a novel antimetastatic role for the PROS1/MERTK axis in myeloid-derived cells.
• PROS1 acts as a potent regulator of adaptive immune responses, suppressing metastatic seeding.
• PROS1-mediated regulation of IL-10 differs from its regulation of TNF-α and IL-6, suggesting distinct signaling pathways.