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

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

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 3

Pros1-deficient F4/80+ bone marrow–derived cells infiltrate metastatic lungs and impose inflammation in vivo.

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Pros1-deficient F4/80+ bone marrow–derived cells infiltrate metastatic ...
(A–C) Analysis of lung-infiltrating immune cells in tumor-bearing mice. F4/80+ cells sorted from metastatic lungs were characterized immunologically (A and B) and by mRNA expression (C). (B) Distribution of CD11b+CD11c+ and Ly6ChiLy6Clo from the indicated mice is shown as mean percentage of F4/80+ cells ± SEM from 7–8 mice/group. (C) Inflammatory cytokine analysis by RT-qPCR of F4/80+ cells isolated from metastatic lungs. Each symbol represents a pool of 7–8 mice/group; 3 independent experiments. Mean relative values ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (P = 0.014, 0.0005, and 0.002 for Il-6, Nos2, and Il-10, respectively); t test. (D–H) Adoptive transfer of Pros1-deficient bone marrow (BM) induces lung inflammation and supports lung metastasis. (D and E) TdT and cytokine expression in lungs 7 weeks after BM transplantation from Pros1+/+ TdT+ into TdT-deficient cKO (green bars) and TdT+-cKO into TdT-deficient Pros1fl/fl (fl/fl, blue bars) in a tumor-naive setting. Mean ± SEM; 4 mice/group. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (P = 0.018, 0.008, and 0.003 for Tnfa, Nos2, and Il-10, respectively); t test. (F–H) LLC-Luc cells were s.c. injected 4 weeks after BM transplantation. Three weeks later, lungs were isolated (F) and analyzed by RT-qPCR (G and H). Mean ± SEM; n = 4–6 mice/group. *P ≤ 0.05, **P < 0.01 (P = 0.002 for Il-10); t test. NS, nonsignificant.