为肝细胞癌武装 GPC3 CAR-T 细胞：多少才足够，下一步是什么？
Armouring GPC3 CAR T cells for hepatocellular carcinoma: how much is enough and what comes next?
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
FXa 介导的 PAR-2 通过诱导 PD-L1 转录，经免疫逃逸和失巢凋亡抵抗促进肝细胞癌免疫治疗的疗效
英文原题：FXa-mediated PAR-2 promotes the efficacy of immunotherapy for hepatocellular carcinoma through immune escape and anoikis resistance by inducing PD-L1 transcription.
查看英文原题
FXa-mediated PAR-2 promotes the efficacy of immunotherapy for hepatocellular carcinoma through immune escape and anoikis resistance by inducing PD-L1 transcription.
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研究概要
FXa 激活的 PAR-2 促进 HCC 中的失巢凋亡抵抗和免疫逃逸，提示联合凝血抑制剂与 PD-1/PD-L1 免疫检查点阻断可能增强 HCC 的治疗效果。
研究思路结论见上方概要
背景
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。在此，我们探讨FXa在调控HCC失巢凋亡抵抗和免疫逃逸中的作用及机制。
方法
进行了体外和体内实验，以探究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。
结果
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通过抑制外源性凋亡通路，使HCC细胞获得抗失巢凋亡能力，从而在循环血液中存活。此外，悬浮刺激诱导的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CD8+ T细胞浸润和分泌细胞因子水平，抑制免疫细胞的抗肿瘤作用。体内使用利伐沙班抑制FXa，可通过降低PD-L1表达和耗竭TIL（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（anti-PD-1）联合在动物模型中诱导了协同抗肿瘤作用。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缓解率，并延长了总生存时间。
展开英文摘要原文
BACKGROUND
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.
METHODS
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.
RESULTS
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 CD8 + T 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.
CONCLUSIONS
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.
论文信息
- 作者
- Li X、Gao L、Wang B、Hu J、Yu Y、Gu B、Xiang L、Li X
- 第一作者单位
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.China
- 通讯作者单位
- Department of Surgical Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China ery_chenh@lzu.edu.cn.China
- 期刊
- Journal for immunotherapy of cancer2024 Jul 25
- 原文标识
- PubMed 39060025 · DOI 10.1136/jitc-2024-009565
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