| Title | Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance |
| Authors | Zhang, Jinfang Bu, Xia Wang, Haizhen Zhu, Yasheng Geng, Yan Nihira, Naoe Taira Tan, Yuyong Ci, Yanpeng Wu, Fei Dai, Xiangpeng Guo, Jianping Huang, Yu-Han Fan, Caoqi Ren, Shancheng Sun, Yinghao Freeman, Gordon J. . Sicinski, Piotr Wei, Wenyi |
| Affiliation | Harvard Med Sch, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA. Harvard Med Sch, Dept Genet, Boston, MA USA. Shanghai Changhai Hosp, Mil Med Univ 2, Dept Urol, Shanghai 200433, Peoples R China. Cent S Univ, Xiangya Hosp 2, Dept Gastroenterol, Changsha 410011, Hunan, Peoples R China. Harbin Inst Technol, Sch Life Sci & Technol, Harbin 150001, Heilongjiang, Peoples R China. Fudan Univ, Huashan Hosp, Dept Urol, Shanghai 200040, Peoples R China. Peking Univ, Sch Life Sci, Acad Adv Interdisciplinary Studies, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China. Harvard Med Sch, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Freeman, GJ (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. Sicinski, P (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA. Sicinski, P (reprint author), Harvard Med Sch, Dept Genet, Boston, MA USA. |
| Keywords | DEPENDENT KINASES PROSTATE-CANCER RETINOBLASTOMA-PROTEIN STABILIZATION IMMUNOTHERAPY REQUIREMENT THERAPY BREAST CELLS SPOP |
| Issue Date | 2018 |
| Publisher | NATURE |
| Citation | NATURE. 2018, 553(7686), 91-+. |
| Abstract | Treatments that target immune 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 with durable clinical benefit(1,2). However, many patients with cancer fail to respond to compounds that target the PD-1 and PD-L1 interaction, and the underlying mechanism(s) is not well understood(3-5). Recent studies revealed that response to PD-1-PD-L1 blockade might correlate with PD-L1 expression levels in tumour cells(6,7). Hence, it is important to understand the mechanistic pathways that control PD-L1 protein expression and stability, which can offer a molecular basis to improve the clinical response rate and efficacy of PD-1-PD-L1 blockade in patients with cancer. Here we show that PD-L1 protein abundance is regulated by cyclin D-CDK4 and the cullin 3-SPOP E3 ligase via proteasome-mediated degradation. Inhibition of CDK4 and CDK6 (hereafter CDK4/6) in vivo increases PD-L1 protein levels by impeding cyclin D-CDK4-mediated phosphorylation of speckle-type POZ protein (SPOP) and thereby promoting SPOP degradation by the anaphase-promoting complex activator FZR1. Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumour-infiltrating lymphocytes in mouse tumours and in primary human prostate cancer specimens. Notably, combining CDK4/6 inhibitor treatment with anti-PD-1 immunotherapy enhances tumour regression and markedly improves overall survival rates in mouse tumour models. Our study uncovers a novel molecular mechanism for regulating PD-L1 protein stability by a cell cycle kinase and reveals the potential for using combination treatment with CDK4/6 inhibitors and PD-1-PD-L1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers. |
| URI | http://hdl.handle.net/20.500.11897/500039 |
| ISSN | 0028-0836 |
| DOI | 10.1038/nature25015 |
| Indexed | SCI(E) |
| Appears in Collections: | 生命科学学院 |
