CDK5 通过伴侣介导的自噬使 PD-L1 不稳定，从而控制肝癌中的肿瘤免疫监视。
CDK5 destabilizes PD-L1 via chaperon-mediated autophagy to control cancer immune surveillance in hepatocellular carcinoma.
机构信息
Cellular and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang, China.
MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
出版信息
J Immunother Cancer. 2023 Nov 24;11(11):e007529. doi: 10.1136/jitc-2023-007529.
BACKGROUND
In the past few years, immunotherapies of hepatocellular carcinoma (HCC) targeting programmed cell death protein 1 (PD-1) and its ligand programmed cell death ligand 1 (PD-L1), have achieved durable clinical benefits. However, only a fraction of HCC patients showed objective clinical response to PD-1/PD-L1 blockade alone. Despite the impact on post-translational modifications of PD-L1 being substantial, its significance in resistance to HCC immunotherapy remains poorly defined.
METHODS
Cyclin-dependent kinase 5 (CDK5) expression was knocked down in HCC cells, CDK5 and PD-L1 protein levels were examined by Western blot. Coimmunoprecipitation was conducted to evaluate the interaction between proteins. Preclinical HCC mice model was constructed to evaluate the effect of CDK5 inhibitor alone or in combination with PD-1 antibody. Clinical HCC samples were used to elucidate the clinical relevance of CDK5, PD-L1, and PD-L1 T290 phosphorylation in HCC.
RESULTS
We find that CDK5 deficiency upregulates PD-L1 protein expression in HCC cells and decipher a novel molecular mechanism under which PD-L1 is downregulated by CDK5, that is, CDK5 mediated PD-L1 phosphorylation at T290 promotes its binding with chaperon protein heat-shock cognate protein 70 (HSC70) and degradation through chaperon-mediated autophagy. Notably, treatment of CDK5 inhibitor, PNU112455A, effectively upregulates the tumorous PD-L1 level, promotes the response to anti-PD-1 immunotherapy,and prolongs the survival time of mice bearing HCC tumors. What is more, the T290 phosphorylation status of PD-L1 correlates with the prognosis of HCC.
CONCLUSIONS
Targeting CDK5 can synergize with PD-1 blockade to suppress HCC growth, which may have clinical benefits. Our study reveals a unique regulation of the degradation of PD-L1 in HCC, and provides an attractive therapeutic target, a potential drug, and a new prognostic marker for the clinical treatment of HCC.
背景
在过去的几年中，针对程序性细胞死亡蛋白 1（PD-1）及其配体程序性细胞死亡配体 1（PD-L1）的肝细胞癌（HCC）免疫疗法已经取得了持久的临床获益。然而，只有一小部分 HCC 患者对 PD-1/PD-L1 阻断单独表现出客观的临床反应。尽管 PD-L1 的翻译后修饰的影响很大，但它在 HCC 免疫治疗耐药中的意义仍未得到明确界定。
方法
在 HCC 细胞中敲低细胞周期蛋白依赖性激酶 5（CDK5），通过 Western blot 检测 CDK5 和 PD-L1 蛋白水平。进行共免疫沉淀以评估蛋白质之间的相互作用。构建临床前 HCC 小鼠模型以评估 CDK5 抑制剂单独或与 PD-1 抗体联合使用的效果。使用临床 HCC 样本阐明 HCC 中 CDK5、PD-L1 和 PD-L1 T290 磷酸化的临床相关性。
结果
我们发现 CDK5 缺乏会在上皮性 HCC 细胞中上调 PD-L1 蛋白表达，并揭示了一个新的分子机制，即 CDK5 通过 PD-L1 T290 磷酸化下调 PD-L1，该机制是通过伴侣蛋白热休克同源蛋白 70（HSC70）介导的 PD-L1 降解，从而促进其降解。值得注意的是，CDK5 抑制剂 PNU112455A 的治疗可有效上调肿瘤 PD-L1 水平，促进对 PD-1 免疫治疗的反应，并延长携带 HCC 肿瘤的小鼠的存活时间。更重要的是，PD-L1 的 T290 磷酸化状态与 HCC 的预后相关。
结论
靶向 CDK5 可与 PD-1 阻断协同抑制 HCC 生长，可能具有临床获益。我们的研究揭示了 HCC 中 PD-L1 降解的独特调控机制，并为 HCC 的临床治疗提供了有吸引力的治疗靶点、潜在药物和新的预后标志物。
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