Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance
Open accessAbstract
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.
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Several critical proteins including CMTM4, CMTM6, GSK3β, CSN5, CDK4, CDK6, and palmitoylated B3GNT3 have been shown to affect post-translational PD-L1 stability.
“Moreover, several critical proteins including CMTM4, CMTM6, GSK3β, CSN5, CDK4, CDK6, and palmitoylated B3GNT3 have been shown to affect post-translational PD-L1 stability31–36.”
From PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells (2022) · cites this paper as [36]
The SUMMARY (page not provided) shows that CDK4 affects PD-L1 protein abundance and that CDK4/6 inhibitors increase its stability. It also reports that CDK6 depletion did not increase PD-L1; this paper therefore does not support listing CDK6 as an independently demonstrated regulator. The other listed proteins are not established by this paper’s findings. (LLM, conf=0.89)
Experimental — accuracy not yet measuredThe Cullin 3-SPOP E3-ligase complex can directly ubiquitinate PD-L1 in a cell-cycle dependent manner, leading to its degradation.
“the Cullin 3-SPOP E3-ligase complex can directly ubiquitinate PD-L1 in a cell-cycle dependent manner, leading to its degradation [15].”
From Characterizing the molecular regulation of inhibitory immune checkpoints with multimodal single-cell screens (2021) · cites this paper as [15]
Perturbation of the CUL3-SPOP complex interferes with the ubiquitination of PD-L1, directly enhancing its stability and protein expression level.
“First, as previously described [15], perturbation of the CUL3-SPOP complex interferes with the ubiquitination of PD-L1, directly enhancing its stability and protein expression level.”
From Characterizing the molecular regulation of inhibitory immune checkpoints with multimodal single-cell screens (2021) · cites this paper as [15]
Perturbation of MYC and CUL3 both increased PD-L1 protein levels, consistent with previous reports.
“we verified that perturbation of BHLH transcription factor MYC [12] and the ubiquitin ligase CUL3 [15] both increased PD-L1 protein levels, consistent with previous reports.”
From Characterizing the molecular regulation of inhibitory immune checkpoints with multimodal single-cell screens (2021) · cites this paper as [15]
CDK4 phosphorylates SPOP, an adaptor for a cullin 3 E3 ubiquitin ligase that binds PD-L1.
“CDK4 was shown to have kinase activity towards SPOP, a cullin 3 E3 ubiquitin ligase adaptor protein that can interact with PD-L1 (Zhang et al., 2018).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Zhang et al., 2018
Palbociclib treatment inhibits SPOP phosphorylation, promotes SPOP degradation, and blocks proteasome-mediated degradation of PD-L1.
“Treatment with palbociclib inhibits SPOP phosphorylation, promoting its degradation and blocking PD-L1 proteasome mediated degradation.”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Zhang et al., 2018
In mouse xenograft models of colon adenocarcinoma, adding PD-1 blockade to palbociclib improved tumor regression and overall survival.
“Combining palbociclib with a PD-1 blockade enhanced tumor regression and improved overall survival in mouse xenograft models of colon adenocarcinoma (Deng et al., 2017; Zhang et al., 2018).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Zhang et al., 2018
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- Authors
- Zhang, J., Bu, X., Wang, H., Zhu, Y., Geng, Y., Nihira, N. T., Tan, Y., Ci, Y., Wu, F., Dai, X., Guo, J., Huang, Y.-H., Fan, C., Ren, S., Sun, Y., Freeman, G. J., Sicinski, P., & Wei, W.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Second Military Medical University (CN)
- Corresponding author
- Freeman, Gordon J.
- Wei, Wenyi
- ORCID
- Venue
- Nature
- Published
- 2017-11-16
- Volume
- 553
- Issue
- 7686
- Pages
- 91-95
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5754234
- OpenAlex
- W2769376007
- Cited by
- 1,013
- References
- 43
- Citations by year
- 2026: 81 · 2025: 123 · 2024: 138 · 2023: 140 · 2022: 134 · 2021: 157 · 2020: 118 · 2019: 78 · 2018: 43
- FWCI
- 28.82
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-07-03)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (R01CA190509, R01CA229307, R01CA200573, K99CA212292, R01CA177910, P50CA101942, R01CA132740, R01CA202634, P01CA080111, R01CA200651, R01CA083688)
- National Institute of General Medical Sciences (R01GM094777, R01GM089763)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- PD-L1, anti-PD-1 therapy, CDK4/6 inhibitors, FZR1, proteasomal degradation, polyubiquitination, tumor immune evasion, immune checkpoint blockade, combination immunotherapy, tumor immune microenvironment
- MeSH terms
- Animals, Cell Cycle, Cell Line, Female, Humans, Immunologic Surveillance, Male, Neoplasms, Nuclear Proteins, Phosphorylation, Prostatic Neoplasms, Repressor Proteins, Lymphocytes, Tumor-Infiltrating, Tumor Escape, Cullin Proteins, Proteasome Endopeptidase Complex, 14-3-3 Proteins, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Mice, Protein Stability, Cyclin D, Proteolysis, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Cdh1 Proteins
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