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.

中文翻译：

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凝血酶通过血小板结合的GARP的蛋白水解作用激活LTGF-β，有助于逃避癌症。

在进行性癌症患者中经常观察到与癌症有关的血小板增多和高浓度的循环转化生长因子-β1（TGF-β1）。使用遗传学和药理学方法，我们显示了凝血酶催化活性和血小板释放成熟TGF-β1之间的直接联系。我们发现凝血酶裂解主要的糖蛋白A重复（GARP），这是血小板上潜在TGF-β1（LTGF-β1）的细胞表面对接受体，导致活性TGF-β1从GARP-LTGF-β1复合物中释放出来。此外，凝血酶的全身性抑制作用消除了血小板释放物中TGF-β1的成熟，并使肿瘤微环境重新趋向于良好的抗肿瘤免疫力，它可以单独或与基于程序性细胞死亡1的免疫检查点封锁疗法联合使用，有效控制癌症。最后，我们证明了可溶性GARP和GARP-LTGF-β1复合物存在于癌症患者的血液中。总之，我们的数据揭示了癌症免疫逃逸的机制，该机制涉及凝血酶介导的GARP裂解和随后的TGF-β1从血小板释放。我们建议，阻断GARP裂解是一种有价值的治疗策略，可以克服癌症对免疫疗法的抵抗力。