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 revealed an unexpected antimetastatic role for myeloid-derived PROS1: suppressing metastatic potential in lung and breast tumor models. Pros1 deletion in myeloid cells led to increased lung metastasis, independent of primary tumor infiltration. PROS1-cKO bone marrow–derived macrophages (BMDMs) led to elevated TNF-α, IL-6, Nos2, and IL-10 via modulation of the Socs3/NF-κB 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 DCs in a PROS1-dependent manner. Inhibition of MERTK kinase activity blocked PROS1-mediated suppression of TNF-α and IL-6 but not IL-10. Overall, using lung and breast cancer models, we identified the PROS1/MERTK axis within BMDMs as a potent regulator of adaptive immune responses with a potential to suppress metastatic seeding and revealed IL-10 regulation by PROS1 to deviate from that of TNF-α and IL-6.
Bibliographical noteFunding Information:
This study was supported by a Research Career Development Award and by a project grant from the Israel Cancer Research Fund (ICRF) to TBC, a research grant by the Israel Cancer Association (ICA) and funded by the Golombo Foundation to TBC, and an ICRF booster grant to AM. SL is funded by a Heisenberg professorship (LO1863/4-1) and by the ubone SPP program (LO1863/5-1) awarded by the German Research Council. Furthermore, SL receives funding from the Margarete-Clemens Stfitung. We thank Nikita Gvardiyan and Shira Kaikov for technical support; and Yaara Tabib, Oded Hayman, Noam Koren, and Avi-Hai Hovav for assisting with FACS experiments and analysis. We also thank Hadas Masuri and Zhanna Yekhtin for experimental support and Zvi Granot for providing cancer cell lines. We thank Xiaodong Wang, University of North Carolina, for providing the anti-TAM inhibitors.
© 2021, American Society for Clinical Investigation.