Cyclin D-CDK4 kinase destabilizes PD-L1 via Cul3SPOP to control cancer immune surveillance
By Jinfang Zhang, Xia Bu, Haizhen Wang, Yasheng Zhu, Y. Geng, N. T. Nihira, Yuyong Tan, Yanpeng Ci, Fei Wu, Xiangpeng Dai and 8 more. Nature, 2017
762 citations recorded by the source corpus.
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. 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. Recent studies revealed that response to PD-1–PD-L1 blockade might correlate with PD-L1 expression levels in tumour cells. 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.
Subfields: Oncology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/5ff806760f430267c3832e5544acb409dfe3e7ee
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Citations in the corpus
- Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition (2021, neutral): “Specifically, Zhang et al. (2018) demonstrated that PDL1 protein abundance fluctuates during cell-cycle progression and that Cyclin D-CDK4 negatively regulates PD-L1 protein stability.”
- Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors (2018, background): “However, PD-1/PD-L1 axis influence the balance between tumor immune surveillance and immune resistance as well [12, 13].”
- The role of ubiquitination in tumorigenesis and targeted drug discovery (2020, background): “For example, the stability of PD-L1 is regulated by SPOP via proteasome-mediated degradation in cancer cells.(500) FBXO38, an E3 ligase of PD-1, mediates K48-linked polyubiquitination and subsequent proteasome degradation in activated T cells.”