Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany.
Department of Immunology and Microbiology, Scripps Research, La Jolla, CA, USA.
Sci Immunol. 2019 Sep 20;4(39). doi: 10.1126/sciimmunol.aaw8405.
Immune evasion in the tumor microenvironment (TME) is a crucial barrier for effective cancer therapy, and plasticity of innate immune cells may contribute to failures of targeted immunotherapies. Here, we show that rivaroxaban, a direct inhibitor of activated coagulation factor X (FX), promotes antitumor immunity by enhancing infiltration of dendritic cells and cytotoxic T cells at the tumor site. Profiling FX expression in the TME identifies monocytes and macrophages as crucial sources of extravascular FX. By generating mice with immune cells lacking the ability to produce FX, we show that myeloid cell-derived FX plays a pivotal role in promoting tumor immune evasion. In mouse models of cancer, we report that the efficacy of rivaroxaban is comparable with anti-programmed cell death ligand 1 (PD-L1) therapy and that rivaroxaban synergizes with anti-PD-L1 in improving antitumor immunity. Mechanistically, we demonstrate that FXa promotes immune evasion by signaling through protease-activated receptor 2 and that rivaroxaban specifically targets this cell-autonomous signaling pathway to reprogram tumor-associated macrophages. Collectively, our results have uncovered the importance of FX produced in the TME as a regulator of immune cell activation and suggest translational potential of direct oral anticoagulants to remove persisting roadblocks for immunotherapy and provide extravascular benefits in other diseases.
肿瘤微环境（TME）中的免疫逃逸是癌症治疗的一个关键障碍，先天免疫细胞的可塑性可能导致靶向免疫疗法的失败。在这里，我们表明，直接激活凝血因子 X（FX）抑制剂利伐沙班通过增强树突状细胞和肿瘤部位细胞毒性 T 细胞的浸润来促进抗肿瘤免疫。在 TME 中对 FX 表达进行分析，确定单核细胞和巨噬细胞是血管外 FX 的重要来源。通过生成缺乏产生 FX 能力的免疫细胞的小鼠，我们表明髓样细胞衍生的 FX 在促进肿瘤免疫逃逸中起着关键作用。在癌症的小鼠模型中，我们报告称，利伐沙班的疗效可与抗程序性细胞死亡配体 1（PD-L1）治疗相媲美，并且利伐沙班与抗 PD-L1 联合使用可改善抗肿瘤免疫。从机制上讲，我们证明 FXa 通过蛋白酶激活受体 2 信号转导促进免疫逃逸，而利伐沙班专门针对该细胞自主信号通路，以重新编程肿瘤相关巨噬细胞。总之，我们的研究结果揭示了 TME 中产生的 FX 作为免疫细胞激活调节剂的重要性，并表明直接口服抗凝剂具有转化潜力，可以消除免疫治疗中持续存在的障碍，并在其他疾病中提供血管外益处。
