Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany; Department of Immunology and Microbiology, Scripps Research, La Jolla, CA, USA.
Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany.
Thromb Res. 2020 Jul;191 Suppl 1:S106-S111. doi: 10.1016/S0049-3848(20)30406-0.
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.
过去几十年已经描绘了许多止血系统与癌细胞之间的相互作用，这些作用对癌症相关的血栓形成、血管生成和转移至关重要。越来越多的证据表明，血小板、组织因子途径和涉及蛋白酶激活受体 (PARs) 的蛋白水解信号也在先天和适应性免疫中发挥核心作用。最近在免疫功能正常的小鼠中的研究揭示了凝血信号网络在不同临床前肿瘤模型的发展和生长中具有新的免疫逃避作用。肿瘤类型特异性 PAR1 信号促进了细胞毒性 T 细胞的免疫逃避。此外，肿瘤相关巨噬细胞产生因子 X (FX)，并且细胞自主 FXa-PAR2 信号作为肿瘤微环境中促进肿瘤促进巨噬细胞极化的中心机制出现。用穿透组织的口服 FXa 抑制剂靶向该信号通路可重新编程巨噬细胞表型，增强肿瘤抗原呈递，并扩增杀伤肿瘤的细胞毒性淋巴细胞。重要的是，通过特异性靶向先天免疫细胞，口服 FXa 抑制剂与检查点抑制剂治疗协同作用，增强了抗原特异性抗肿瘤免疫。在类似的实验中，肝素抗凝对阻止血管外凝血信号作用不大。因此，口服 FXa 抑制剂的抗血栓治疗可能有助于逆转肿瘤免疫逃避机制，并提高靶向免疫治疗方案的临床效果。
