Thrombin contributes to cancer immune evasion via proteolysis of platelet-bound GARP to activate LTGF-β

Sci Transl Med. 2020 Jan 8;12(525):eaay4860. doi: 10.1126/scitranslmed.aay4860.


Cancer-associated thrombocytosis and high concentrations of circulating transforming growth factor-β1 (TGF-β1) are frequently observed in patients with progressive cancers. Using genetic and pharmacological approaches, we show a direct link between thrombin catalytic activity and release of mature TGF-β1 from platelets. We found that thrombin cleaves glycoprotein A repetitions predominant (GARP), a cell surface docking receptor for latent TGF-β1 (LTGF-β1) on platelets, resulting in liberation of active TGF-β1 from the GARP-LTGF-β1 complex. Furthermore, systemic inhibition of thrombin obliterates TGF-β1 maturation in platelet releasate and rewires the tumor microenvironment toward favorable antitumor immunity, which translates into efficient cancer control either alone or in combination with programmed cell death 1-based immune checkpoint blockade therapy. Last, we demonstrate that soluble GARP and GARP-LTGF-β1 complex are present in the circulation of patients with cancer. Together, our data reveal a mechanism of cancer immune evasion that involves thrombin-mediated GARP cleavage and the subsequent TGF-β1 release from platelets. We propose that blockade of GARP cleavage is a valuable therapeutic strategy to overcome cancer's resistance to immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Platelets / metabolism*
  • Carcinogenesis / drug effects
  • Carcinogenesis / immunology
  • Carcinogenesis / pathology
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Disease Progression
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Evasion* / drug effects
  • Latent TGF-beta Binding Proteins / blood
  • Latent TGF-beta Binding Proteins / metabolism*
  • Membrane Proteins / metabolism*
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Protein Binding / drug effects
  • Proteolysis* / drug effects
  • Thrombin / metabolism*
  • Tumor Microenvironment / drug effects


  • Immune Checkpoint Inhibitors
  • LRRC32 protein, human
  • Latent TGF-beta Binding Proteins
  • Lrrc32 protein, mouse
  • Membrane Proteins
  • Thrombin