Stimulation of TAM (TYRO3, AXL and MERTK) Receptor Tyrosine Kinases promotes tumor progression through numerous cellular mechanisms. TAM cognate ligands GAS6 and PROS1 (for TYRO3 and MERTK) are secreted by host immune cells, an interaction which may support tumor progression. Here we reveal an unexpected anti-metastatic role for myeloid-derived PROS1, directly suppressing the metastatic potential of lung and breast tumor models. Pros1 deletion in myeloid cells led to increased lung metastasis, independent of primary tumor infiltration. PROS1-cKO BMDMs led to elevated TNFα, IL-6, Nos2 and IL-10 via modulation of the Socs3-NFκB pathway. Conditioned medium from cKO BMDMs enhanced EMT, ERK, AKT and STAT3 activation within tumor cells, and promoted IL-10 dependent invasion and survival. Macrophages isolated from metastatic lungs modulated T cell proliferation and function, as well as expression of costimulatory molecules on dendritic cells in a PROS1-dependent manner. Inhibition of MERTK kinase activity blocked PROS1-mediated suppression of TNFα and IL-6, but not of IL-10. Overall, using lung and breast cancer models, we identify the PROS1-MERTK axis within BMDMs as a potent regulator of adaptive immune responses with a potential to suppress metastatic seeding, and reveal IL-10 regulation by PROS1 to deviate from that of TNFα and IL-6.
Avi Maimon, Victor Levi-Yahid, Kerem Ben-Meir, Amit Halpern, Ziv Talmi, Shivam Priya, Gabriel Mizraji, Shani Mistriel-Zerbib, Michael Berger, Michal Baniyash, Sonja Loges, Tal Burstyn-Cohen