The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.
Gansu Provincial Key Laboratory of Environmental Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.
J Immunother Cancer. 2024 Jul 25;12(7):e009565. doi: 10.1136/jitc-2024-009565.
The high metastasis rate is one of the main reasons for the poor prognosis of patients with hepatocellular carcinoma (HCC). Coagulation factor Xa (FXa) and its receptor proteinase-activated receptor-2 (PAR-2) proven to promote tumor metastasis in other forms of cancer. Here, we explore the role and mechanism of FXa in the regulation of resistance of anoikis and immune escape of HCC.
In vitro and in vivo experiments were conducted to explore the role of FXa in HCC metastasis and its potential mechanism. The effects of FXa inhibitor rivaroxaban on HCC immunotherapy were evaluated using intrahepatic metastasis animal models and clinical trial (No. ChiCTR20000040540). We investigated the potential of FXa inhibition as a treatment for HCC.
FXa was highly expressed in HCC and promoted metastasis by activating PAR-2. Mechanistically, FXa-activated PAR-2 endows HCC cells with the ability of anoikis resistance to survive in the circulating blood by inhibiting the extrinsic apoptosis pathway. Furthermore, suspension stimulation-induced phosphorylation of STAT2, which promotes programmed death-ligand 1 (PD-L1) transcription and inhibits the antitumor effects of immune cells by inhibiting the infiltration of CD8T cells in tumors and the levels of secreted cytokines. In vivo inhibition of FXa with rivaroxaban reduced HCC metastasis by decreasing PD-L1 expression and exhausting tumor-infiltrating lymphocytes. Notably, the combination of rivaroxaban and anti-programmed death-1 monoclonal antibody (anti-PD-1) programmed Death-1 monoclonal antibody (anti-PD-1) induced synergistic antitumor effects in animal models. Most importantly, rivaroxaban improved the objective response rate of patients with HCC to immune checkpoint inhibitors and prolonged overall survival time.
FXa-activated PAR-2 promotes anoikis resistance and immune escape in HCC, suggesting the potential for combining coagulation inhibitors and PD-1/PD-L1 immune checkpoint blockade to enhance the therapeutic efficacy of HCC.
高转移率是肝细胞癌（HCC）患者预后不良的主要原因之一。凝血因子 Xa（FXa）及其受体蛋白酶激活受体-2（PAR-2）已被证明可促进其他形式癌症的肿瘤转移。在这里，我们探讨了 FXa 在调节 HCC 抵抗失巢凋亡和免疫逃逸中的作用及其机制。
进行了体外和体内实验，以探讨 FXa 在 HCC 转移中的作用及其潜在机制。使用肝内转移动物模型和临床试验（编号 ChiCTR20000040540）评估了 FXa 抑制剂利伐沙班对 HCC 免疫治疗的影响。我们研究了 FXa 抑制作为 HCC 治疗的潜力。
FXa 在 HCC 中高表达，并通过激活 PAR-2 促进转移。机制上，FXa 激活的 PAR-2 通过抑制外在凋亡途径赋予 HCC 细胞在循环血液中存活的抗失巢凋亡能力。此外，悬浮刺激诱导 STAT2 磷酸化，促进程序性死亡配体 1（PD-L1）转录，并通过抑制肿瘤中 CD8T 细胞的浸润和细胞因子的分泌水平抑制免疫细胞的抗肿瘤作用。体内用利伐沙班抑制 FXa 可通过降低 PD-L1 表达和耗竭肿瘤浸润淋巴细胞来减少 HCC 转移。值得注意的是，利伐沙班与抗程序性死亡-1 单克隆抗体（抗 PD-1）联合在动物模型中诱导协同抗肿瘤作用。最重要的是，利伐沙班提高了 HCC 患者对免疫检查点抑制剂的客观反应率并延长了总生存时间。
FXa 激活的 PAR-2 促进 HCC 中的抗失巢凋亡和免疫逃逸，表明联合使用凝血抑制剂和 PD-1/PD-L1 免疫检查点阻断剂有可能增强 HCC 的治疗效果。
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