Nature杂志在线发表了哈佛大学医学院魏文毅教授和Freeman教授以及 Sicinski教授的最新原创研究论著作Cyclin D/CDK4 kinase destabilizes PD-L1 via Cul3/SPOP to control cancer immune surveillance. Nature. 2017 Nov 16. doi:10.1038/ nature 25015。该研究成果主要由哈佛大学医学院完成。

靶向免疫检查点的癌症治疗策略，例如靶向由程序性细胞死亡蛋白1(PD-1)及其配体PD-L1所调控的靶点治疗，目前已被批准应用于临床治疗，并取得了一系列较好的效果。然而，抗PD-1/PD-L1的治疗策略在很多癌症患者中的治疗效果并不理想，并且其潜在机制目前尚不清楚。研究表明针对PD-1/PD-L1的反应阻滞可能与癌细胞中的PD-L1的表达水平密切相关。因此，目前人们迫切的需要系统的阐明调控PD-L1蛋白水平及其稳定性的相关信号通路，而这一信号通路的研究将会为针对PD-1/PD-L1阻滞的治疗提供重要的分子基础，以改善PD-1/PD-L1在癌症患中的临床反应率和有效性。

在本研究中，作者们发现周期蛋白D-CDK4以及Cullin 3相结合的E3连接酶SPOP可以通过蛋白酶体调控降解来控制PD-L1的蛋白水平。在小鼠体内，可以通过抑制CDK4/6的表达以促进PD-L1的蛋白水平，这一调控过程很大程度上是通过抑制周期蛋白D–CDK4所介导的SPOP的磷酸化作用并促进APC/C^Cdh1对于SPOP的降解作用。研究表明在小鼠肿瘤以及人的前列腺癌标本中，发生功能缺失突变的SPOP无法泛素化降解PD-L1，进而增加了PD-L1蛋白水平，并减少了雌激素受体淋巴细胞的数量。值得注意的是，在小鼠肿瘤模型中，结合抑制CDK4/6的抗-PD-1的免疫治疗策略抑制了肿瘤的生长进程并显著提高了总体生存率。

王志伟教授认为该研究揭示了一种全新的通过细胞周期蛋白激酶调控PD-L1蛋白水平的分子机制。苏州大学王志伟教授进一步认为该研究也为人类癌症的治疗提供了一种潜在的策略，即可以通过联合使用CDK4/6抑制剂和PD-1/ PD-L1免疫检查点阻滞来增强人类癌症的治疗效果。

英文摘要

Nature. 2017Nov 16. doi: 10.1038/nature25015. [Epub ahead of print]

Cyclin D-CDK4 kinasedestabilizes PD-L1 via Cul3/SPOP to control cancerimmune surveillance.

Zhang J¹, Bu X², Wang H³, Zhu Y⁴, Geng Y³, Nihira NT¹, Tan Y^1,5, Ci Y^1,6, Wu F^1,7, Dai X¹, Guo J¹, Huang YH¹, Fan C^3,8, Ren S⁴, Sun Y⁴, Freeman GJ², Sicinski P³, Wei W¹.

Author information

Abstract

Treatments that targetimmune checkpoints, such as the one mediated by programmed cell death protein 1(PD-1) and its ligand PD-L1, have been approved for treating human cancers withdurable clinical benefit^1,2. However, many cancer patients fail to respond toanti-PD-1/PD-L1 treatment, and the underlying mechanism(s) is not wellunderstood^3-5. Recent studies revealedthat response to PD-1/PD-L1 blockade might correlate with PD-L1 expressionlevels in tumor cells^6,7. Hence, it is important tomechanistically understand the pathways controlling PD-L1 protein expressionand stability, which can offer a molecular basis to improve the clinicalresponse rate and efficacy of PD-1/PD-L1 blockade in cancer patients. Here, wereport that PD-L1 protein abundance is regulated by cyclin D-CDK4 and theCullin 3^SPOP E3 ligase viaproteasome-mediated degradation. Inhibition of CDK4/6 in vivo elevates PD-L1protein levels, largely by inhibiting cyclin D-CDK4-mediated phosphorylation ofSPOP and thereby promoting SPOP degradation by APC/C^Cdh1. Loss-of-functionmutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leadingto increased PD-L1 levels and reduced numbers of tumor-infiltrating lymphocytes(TILs) in mouse tumors and in primary human prostate cancer specimens. Notably,combining CDK4/6 inhibitor treatment with anti-PD-1 immunotherapy enhancestumor regression and dramatically improves overall survival rates in mousetumor models. Our study uncovers a novel molecular mechanism for regulatingPD-L1 protein stability by a cell cycle kinase and reveals the potential forusing combination treatment with CDK4/6 inhibitors and PD-1/PD-L1 immunecheckpoint blockade to enhance therapeutic efficacy for human cancers.