Nature杂志2017年11月16号在线发表了通讯作者为哈佛大学医学院魏文毅教授和Freeman教授以及Sicinski教授的研究论著（doi: 10.1038/nature25015.） 该研究成果主要由哈佛大学医学院完成。

免疫治疗已经被人们认可，而且在临床上也显示出不错的疗效，靶向由程序性细胞死亡蛋白1(PD-1)及其配体PD-L1所参与的肿瘤治疗，尽管有效，但是许多时候病人没有表现出积极的免疫反应。因此阐明患者对PD-1/PD-L1反应不敏感的机制对临床有重要的意义。这篇研究中作者们发现cyclinD-CDK4 和SPOP，一种Cullin3相结合的E3连接酶，可以调控PD-L1的蛋白水平。细胞株试验非常清楚地证明了他们的观点。小鼠实验也进一步表明可以通过抑制CDK4/6的表达来促进PD-L1的蛋白水平。抑制cyclinD-CDK4介导的SPOP磷酸化作用可以促进CDH1对SPOP的降解作用。

在小鼠和人前列腺癌标本中，SPOP突变导致功能缺失后，无法降解PD-L1，结果增加了PD-L1蛋白水平，降低了肿瘤浸润淋巴细胞。进一步该研究发现在小鼠模型，联合使用CDK4/6抑制剂和抗PD-1免疫治疗后抑制了肿瘤生长和显著提高小鼠的生存率。魏文毅教授团队的工作进一步阐明了细胞周期激酶调控PD-L1的新的分子机制。也为联合使用CDK4/6抑制剂和抗PD-1/PD-L1免疫治疗提供了理论基础。

英文摘要

Nature. 2017 Nov 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.