Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
J Immunother Cancer. 2020 Oct;8(2). doi: 10.1136/jitc-2020-001377.
2,5-dimethylcelecoxib (DMC) is a targeted inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1), a key enzyme in the PGE2 synthesis pathway of inflammatory mediators. Previous studies have confirmed that DMC can inhibit the growth of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, it is not known whether DMC is involved in the changes of tumor immune microenvironment.
In this study, we explored the effects of DMC on HBV-related HCC immune microenvironment, and deeply analyzed its unique effect and mechanism on programmed death receptor 1 (PD-1)/and its ligand 1 (PD-L1) pathway.
Clinical hepatoma tissues detection showed that compared with non-virus-related HCC, the level of CD8 of HBV-related HCC was significantly lower, while the levels of PD-L1 and CD163 were higher. In vivo experiments indicated that DMC could increase the level of tumor infiltrating CD8 T cells in hepatitis B virus X (HBx) (+) hepatoma cells implanted mouse models, and inhibit the expression of PD-L1 and CD163 in tumor tissues. DMC combined with atezolizumab had more significant antitumor effect and stronger blocking effect on PD-1/PD-L1 pathway. Mechanism studies have shown that DMC can promote ubiquitin degradation of HBx-induced PD-L1 protein in HCC cells by activating adenosine 5'-monophosphate-activated protein kinase pathway. Further experiments confirmed that this process was mainly mediated by E3 ligase RBX1.
Our results uncover a role for DMC in promoting HBV-related HCC immune microenvironment, which not only enrich the relationship between inflammatory factors (mPGES-1/PGE2 pathway) and immunosuppression (PD-L1), but also provide an important strategic reference for multitarget or combined immunotherapy of HBV-related HCC.
2,5-二甲基塞来昔布（DMC）是一种靶向抑制微粒体前列腺素 E 合酶-1（mPGES-1）的药物，mPGES-1 是炎症介质中 PGE2 合成途径的关键酶。先前的研究已经证实，DMC 可以抑制乙型肝炎病毒（HBV）相关肝细胞癌（HCC）的生长。然而，目前尚不清楚 DMC 是否参与肿瘤免疫微环境的变化。
在本研究中，我们探讨了 DMC 对 HBV 相关 HCC 免疫微环境的影响，并深入分析了其对程序性死亡受体 1（PD-1）及其配体 1（PD-L1）通路的独特作用和机制。
临床肝癌组织检测显示，与非病毒相关 HCC 相比，HBV 相关 HCC 的 CD8 水平明显降低，而 PD-L1 和 CD163 的水平较高。体内实验表明，DMC 可增加乙型肝炎病毒 X（HBx）（+）肝癌细胞植入小鼠模型中肿瘤浸润性 CD8 T 细胞的水平，并抑制肿瘤组织中 PD-L1 和 CD163 的表达。DMC 联合阿替利珠单抗具有更显著的抗肿瘤作用，并对 PD-1/PD-L1 通路具有更强的阻断作用。机制研究表明，DMC 通过激活 AMPK 通路可促进 HCC 细胞中 HBx 诱导的 PD-L1 蛋白的泛素降解。进一步的实验证实，这一过程主要是由 E3 连接酶 RBX1 介导的。
我们的研究结果揭示了 DMC 在促进 HBV 相关 HCC 免疫微环境中的作用，不仅丰富了炎症因子（mPGES-1/PGE2 通路）与免疫抑制（PD-L1）之间的关系，而且为 HBV 相关 HCC 的多靶点或联合免疫治疗提供了重要的战略参考。
