威廉希尔学术报告
题目: Targeting kinases and immune checkpoints for cancer therapy
演讲人：Jinfang Zhang, Ph.D.,
Instructor, Department of Pathology,
Beth Israel Deaconess Medical Center,
Harvard Medical School
时间：2018年6月19日15:00-16:00
地点：金光生命科学大楼311
摘要:
Immunotheraphy with blockade of programmed cell death protein 1 (PD-1) and its ligand PD-L1 has been approved for treating several cancer types with durable clinical benefit. However, majority of cancer patients fail to respond to the single anti-PD-1/PD-L1 agent treatment, and the underlying mechanism(s) is not well understood. Recent studies revealed that response to PD-1/PD-L1 blockade might correlate with PD-L1 expression levels in tumor cells. Hence, it is important to mechanistically understand the pathways controlling 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 cancer patients.
Our study showed that PD-L1 protein abundance fluctuates during cell cycle, and further identify the cell cycle kinase cyclin D-CDK4 activity play a crucial role in destabilizing PD-L1. Mechanistically, we characterize Cullin 3SPOP as the physiological ubiquitin E3 ligase of PD-L1 and further demonstrates that the cyclin D-CDK4 stabilizes SPOP in a phosphorylation-dependent manner. As such, CDK4/6 inhibitor (Palbociclib) treatment destabilizes SPOP to increase PD-L1 protein abundance to possibly induce immune evasion.
Pathologically, loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to 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 kinase inhibitor (Palbociclib) treatment with anti-PD-1 immunotherapy enhances tumor regression and dramatically improves overall survival rates in mouse tumor 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. This work has been published at Nature (Zhang J. et. al., Nature, 2018; 553(7686): 91-95).
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