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

Cancer-associated thrombocytosis and high concentrations of circulating transforming growth factor-beta 1 (TGF-beta 1) 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-beta 1 from platelets. We found that thrombin cleaves glycoprotein A repetitions predominant (GARP), a cell surface docking receptor for latent TGF-beta 1 (LTGF-beta 1) on platelets, resulting in liberation of active TGF-beta 1 from the GARP-LTGF-beta 1 complex. Furthermore, systemic inhibition of thrombin obliterates TGF-beta 1 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-beta 1 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-beta 1 release from platelets. We propose that blockade of GARP cleavage is a valuable therapeutic strategy to overcome cancer's resistance to immunotherapy.