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Myeloid cell–derived PROS1 inhibits tumor metastasis by regulating inflammatory and immune responses via IL-10
Avi Maimon, … , Sonja Loges, Tal Burstyn-Cohen
Avi Maimon, … , Sonja Loges, Tal Burstyn-Cohen
Published April 13, 2021
Citation Information: J Clin Invest. 2021;131(10):e126089. https://doi.org/10.1172/JCI126089.
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Research Article Inflammation Oncology Article has an altmetric score of 34

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

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Abstract

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.

Authors

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

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Figure 5

Enhanced metastatic potency of Pros1-deficient BMDMs.

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Enhanced metastatic potency of Pros1-deficient BMDMs.
(A–C) LLC cells we...
(A–C) LLC cells were educated for 24 hours with conditioned medium (CM) of BMDMs isolated from nontumor (NT) or tumor-bearing (T) control (Pros1fl/fl) and Pros1-cKO mice. Educated cells were injected into WT mice. Lung metastases (Mets) were evaluated at 3 weeks by H&E. Representative H&E-stained lung sections (A), average area (B; **P = 0.01 for NT; ***P = 0.001 for T), and number of metastases (C; *P = 0.05 for NT; nonsignificant for T) are plotted. n = 8–10 mice/group; t test. (D–F) GFP-labeled AT3 cells were educated for 96 hours with the indicated BMDM-CM and injected into host WT mice. Lung metastases were evaluated 3 weeks later. n = 8 mice/group. Representative H&E lung sections (D), average metastatic area (E), and number (F) are shown. The horizontal line represents the mean value. *P < 0.05 (=0.02), **P = 0.01; t test. Scale bars: 200 μm. (G and H) Representative images of freshly isolated lungs described in D as observed under bright field (BF) and fluorescent illumination (GFP). Arrows indicate metastatic foci. Scale bars: 2 mm. (H) Representative Western blot for GFP content in lungs shown in G. GAPDH was used as a loading control. n = 4/group.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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