School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
Gut. 2018 May;67(5):931-944. doi: 10.1136/gutjnl-2017-314032. Epub 2017 Sep 22.
OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC). DESIGN: Immunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific -inducible transgenic (TG) mice and Hepa1-6 orthotopic HCC models using CRISPR/Cas9-mediated depletion and liver-targeted nanoparticles for interleukin (IL) 6 trapping. Tumorigenicity and immunophenotype were assessed on single or combined antiprogrammed death-1-ligand 1 (PD-L1) therapy. RESULTS: Tumour-infiltrating CD11bCD33HLA-DR MDSCs from patients with HCC potently inhibited autologous CD8T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11bCD33HLA-DR MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-κB (NF-κB) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-κB-EZH2 co-binding to promoter. Hepatic induction in TG mice activated the EZH2/NF-κB/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. In contrast, inhibiting tumorous or hepatic IL-6 increased interferon γtumour necrosis factor-αCD8 T cell infiltration and impaired tumorigenicity, which was rescued by restoring PMN-MDSCs. Notably, tumorous depletion upregulated PD-L1 expression and increased intratumorous CD8 T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC. CONCLUSION: Our results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.
目的：髓源性抑制细胞（MDSCs）有助于肿瘤免疫抑制微环境和免疫检查点阻断耐药。新出现的证据强调了细胞周期蛋白依赖性激酶（CDKs）在肿瘤免疫中的关键作用。在这里，我们阐明了肿瘤内在的 CDK20 或细胞周期相关激酶（CCRK）在肝细胞癌（HCC）中的免疫抑制作用。 设计：通过流式细胞术、表达分析和共培养系统确定来自 HCC 患者的 MDSC 的免疫抑制作用及其与 CCRK 的关系。还使用肝特异性诱导型转基因（TG）小鼠和 Hepa1-6 原位 HCC 模型，通过 CRISPR/Cas9 介导的耗竭和用于白细胞介素（IL）6 捕获的肝靶向纳米颗粒进行机制研究。评估了单一或联合抗程序性死亡配体 1（PD-L1）治疗的致瘤性和免疫表型。 结果：来自 HCC 患者的肿瘤浸润性 CD11bCD33HLA-DR MDSC 强烈抑制自身 CD8T 细胞增殖。CCRK 和 MDSC 标志物（CD11b/CD33）的一致过表达与较差的生存率呈正相关。肝细胞 CCRK 通过上调白细胞介素（IL）6 刺激来自人外周血单核细胞的免疫抑制性 CD11bCD33HLA-DR MDSC 扩增。从机制上讲，CCRK 通过增强子结合锌指蛋白 2（EZH2）激活核因子-κB（NF-κB），并促进 NF-κB-EZH2 共同结合到 启动子。在 TG 小鼠中，肝诱导激活了 EZH2/NF-κB/IL-6 级联反应，导致具有强大 T 细胞抑制活性的多形核（PMN）MDSC 积累。相比之下，抑制肿瘤或肝 IL-6 增加了干扰素γ肿瘤坏死因子-αCD8T 细胞浸润并损害了肿瘤发生能力，而通过恢复 PMN-MDSC 则可以挽救。值得注意的是，肿瘤耗竭上调了 PD-L1 表达并增加了肿瘤内 CD8T 细胞，从而增强了 PD-L1 阻断的疗效以根除 HCC。 结论：我们的结果描绘了肝癌内在 CCRK 信号的免疫抑制机制，并强调了一种过表达的激酶靶标，其抑制可能增强 HCC 免疫治疗。
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