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

J Clin Invest. 2021 May 17;131(10):e126089. doi: 10.1172/JCI126089.

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.

Keywords: Inflammation; Macrophages; Oncology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / immunology*
  • Female
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology*
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology*
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / immunology*
  • Mice
  • Neoplasm Metastasis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor-Associated Macrophages / immunology*

Substances

  • Calcium-Binding Proteins
  • IL10 protein, mouse
  • Interleukin-6
  • Neoplasm Proteins
  • Pros1 protein, mouse
  • Tumor Necrosis Factor-alpha
  • interleukin-6, mouse
  • Interleukin-10

Grants and funding

To TBC