Research ArticleCancer

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

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Science Translational Medicine  08 Jan 2020:
Vol. 12, Issue 525, eaay4860
DOI: 10.1126/scitranslmed.aay4860

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Targeting platelets’ darker side

High numbers of platelets can be observed in the setting of advanced cancer, increasing the risk of blood clots. Metelli et al. now demonstrate that platelets also play a more direct role in cancer-associated damage, contributing to tumor growth and immune escape. Thrombin, a serum protein involved in blood coagulation, detaches a cytokine called TGF-β1 from its binding sites on the platelet surface. This results in the release of active TGF-β1, which suppresses the antitumor immune response. The authors also identified a drug that could be repurposed to inhibit this process of TGF-β1 release and demonstrated its efficacy in treating immunocompetent mouse models of cancer.

Abstract

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.

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