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

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

doi:10.1172/JCI126089

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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

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.

Original language	American English
Article number	e126089
Journal	Journal of Clinical Investigation
Volume	131
Issue number	10
DOIs	https://doi.org/10.1172/JCI126089
State	Published - May 2021

Bibliographical note

Funding 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.

Publisher Copyright:
© 2021, American Society for Clinical Investigation.

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10.1172/JCI126089

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Maimon, A., Levi-Yahid, V., Ben-Meir, K., Halpern, A., Talmi, Z., Priya, S., Mizraji, G., Mistriel-Zerbib, S., Berger, M., Baniyash, M., Loges, S., & Burstyn-Cohen, T. (2021). Myeloid cell–derived PROS1 inhibits tumor metastasis by regulating inflammatory and immune responses via IL-10. Journal of Clinical Investigation, 131(10), Article e126089. https://doi.org/10.1172/JCI126089

@article{f9257f0277384fd7a60bb191177d1185,

title = "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.",

author = "Avi Maimon and Victor Levi-Yahid and Kerem Ben-Meir and Amit Halpern and Ziv Talmi and Shivam Priya and Gabriel Mizraji and Shani Mistriel-Zerbib and Michael Berger and Michal Baniyash and Sonja Loges and Tal Burstyn-Cohen",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",

year = "2021",

month = may,

doi = "10.1172/JCI126089",

language = "American English",

volume = "131",

journal = "Journal of Clinical Investigation",

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publisher = "The American Society for Clinical Investigation",

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}

Maimon, A, Levi-Yahid, V, Ben-Meir, K, Halpern, A, Talmi, Z, Priya, S, Mizraji, G, Mistriel-Zerbib, S, Berger, M , Baniyash, M, Loges, S & Burstyn-Cohen, T 2021, 'Myeloid cell–derived PROS1 inhibits tumor metastasis by regulating inflammatory and immune responses via IL-10', Journal of Clinical Investigation, vol. 131, no. 10, e126089. https://doi.org/10.1172/JCI126089

TY - JOUR

T1 - Myeloid cell–derived PROS1 inhibits tumor metastasis by regulating inflammatory and immune responses via IL-10

AU - Maimon, Avi

AU - Levi-Yahid, Victor

AU - Ben-Meir, Kerem

AU - Halpern, Amit

AU - Talmi, Ziv

AU - Priya, Shivam

AU - Mizraji, Gabriel

AU - Mistriel-Zerbib, Shani

AU - Berger, Michael

AU - Baniyash, Michal

AU - Loges, Sonja

AU - Burstyn-Cohen, Tal

N1 - Funding 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. Publisher Copyright: © 2021, American Society for Clinical Investigation.

PY - 2021/5

Y1 - 2021/5

N2 - 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.

AB - 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.

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U2 - 10.1172/JCI126089

DO - 10.1172/JCI126089

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SN - 0021-9738

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JO - Journal of Clinical Investigation

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

Abstract

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