Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune response

J Clin Invest. 2018 Jun 1;128(6):2356-2369. doi: 10.1172/JCI97354. Epub 2018 Apr 30.


Tyro3, Axl, Mer (TAM) receptor tyrosine kinases reduce inflammatory, innate immune responses. We demonstrate that tumor-secreted protein S (Pros1), a Mer/Tyro3 ligand, decreased macrophage M1 cytokine expression in vitro and in vivo. In contrast, tumor cells with CRISPR-based deletion of Pros1 failed to inhibit M1 polarization. Tumor cell-associated Pros1 action was abrogated in macrophages from Mer- and Tyro3- but not Axl-KO mice. In addition, several other murine and human tumor cell lines suppressed macrophage M1 cytokine expression induced by IFN-γ and LPS. Investigation of the suppressive pathway demonstrated a role for PTP1b complexing with Mer. Substantiating the role of PTP1b, M1 cytokine suppression was also lost in macrophages from PTP1b-KO mice. Mice bearing Pros1-deficient tumors showed increased innate and adaptive immune infiltration, as well as increased median survival. TAM activation can also inhibit TLR-mediated M1 polarization. Treatment with resiquimod, a TLR7/8 agonist, did not improve survival in mice bearing Pros1-secreting tumors but doubled survival for Pros1-deleted tumors. The tumor-derived Pros1 immune suppressive system, like PD-L1, was cytokine responsive, with IFN-γ inducing Pros1 transcription and secretion. Inhibition of Pros1/TAM interaction represents a potential novel strategy to block tumor-derived immune suppression.

Keywords: Cancer; Cancer immunotherapy; Cell Biology; Immunology; Immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • Calcium-Binding Proteins
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Cytokines / genetics
  • Cytokines / immunology
  • Humans
  • Imidazoles / pharmacology
  • Macrophages / immunology*
  • Macrophages / pathology
  • Membrane Glycoproteins / agonists
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Knockout
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / pathology
  • Toll-Like Receptor 7 / agonists
  • Toll-Like Receptor 7 / genetics
  • Toll-Like Receptor 7 / immunology
  • Toll-Like Receptor 8 / agonists
  • Toll-Like Receptor 8 / genetics
  • Toll-Like Receptor 8 / immunology


  • B7-H1 Antigen
  • Calcium-Binding Proteins
  • Carrier Proteins
  • Cd274 protein, mouse
  • Cytokines
  • Imidazoles
  • Membrane Glycoproteins
  • Pros1 protein, mouse
  • TLR8 protein, mouse
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • resiquimod