Coagulation signaling and cancer immunotherapy. Issue 191 (July 2020)

• Record Type: Journal Article
• Authors: Ruf, Wolfram; Graf, Claudine
• Is Part Of: Thrombosis research. Issue 191(2020)Supplement 1
• Page Start: S106
• Page End: S111
• Publication Date: 2020-07
• Subjects: Protease-activated receptors -- Coagulation factor -- Xa -- Oral anticoagulants -- Tumor immune evasion -- Checkpoint inhibitor therapy; Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/S0049-3848(20)30406-0
• Languages: English
• ISSNs: 0049-3848

Abstract

ABSTRACT: The last decades have delineated many interactions of the hemostatic system with cancer cells that are pivotal for cancer-associated thrombosis, angiogenesis and metastasis. Expanding evidence shows that platelets, the tissue factor pathway, and proteolytic signaling involving protease-activated receptors (PARs) are also central players in innate and adaptive immunity. Recent studies in immune-competent mice have uncovered new immune-evasive roles of coagulation signaling networks in the development and growth of different preclinical tumor models. Tumor-type specific PAR1 signaling facilitates the escape from immune surveillance by cytotoxic T cells. In addition, tumor-associated macrophages produce factor X (FX) and cell autonomous FXa–PAR2 signaling emerges as a central mechanism for tumor-promoting macrophage polarization in the tumor microenvironment. Pharmacological targeting of this signaling pathway with tissue penetrating oral FXa inhibitor reprograms macrophage phenotypes, enhances tumor antigen presentation, and expands tumor-killing cytotoxic lymphocytes. Importantly, by specifically targeting innate immune cells, the oral FXa inhibitor rivaroxaban synergizes with checkpoint inhibitor therapy in enhancing antigen-specific antitumor immunity. In similar experiments, anticoagulation with heparin is inefficient to block extravascular coagulation signaling. Thus, antithrombotic therapy with oral FXa inhibitors may contribute to reversing tumor immune-evasive mechanisms and enhance the clinical outcome of targeted immuno-therapy regimens.