The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index.
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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“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]
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“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]
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“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]
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“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]
In the citing paper
“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
In the citing paper
“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 the citing paper
“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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Cites
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An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
Soucy, T. A., Smith, P. G., Milhollen, M. A., Berger, A. J., Gavin, J. M., Adhikari, S., Brownell, J. E., Burke, K. E., Cardin, D. P., Critchley, S., et al. (2009) · Nature · doi:10.1038/nature07884 · Cited by 1,990
Self-citationTaxol stabilizes microtubules in mouse fibroblast cells.
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Cell cycle proteins as promising targets in cancer therapy
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Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer
Barbieri, C. E., Baca, S. C., Lawrence, M. S., Demichelis, F., Blattner, M., Theurillat, J.-P. P., White, T. A., Stojanov, P., Allen, E. M. V., Stransky, N., et al. (2012) · Nature Genetics · doi:10.1038/ng.2279 · Cited by 1,550
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Regulation and Function of the PD-L1 Checkpoint
Sun, C., Mezzadra, R., & Schumacher, T. N. (2018) · Immunity · doi:10.1016/j.immuni.2018.03.014 · Cited by 2,248
Immune checkpoint signaling and cancer immunotherapy
He, X., & Xu, C. (2020) · Cell Research · doi:10.1038/s41422-020-0343-4 · Cited by 1,431
Mechanisms Controlling PD-L1 Expression in Cancer
Cha, J., Chan, L.-C., Li, C., Hsu, J. L., & Hung, M. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.09.030 · Cited by 1,076
Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition
Litchfield, K., Reading, J. L., Puttick, C., Thakkar, K., Abbosh, C., Bentham, R., Watkins, T. B. K., Rosenthal, R., Biswas, D., Rowan, A., et al. (2021) · Cell · doi:10.1016/j.cell.2021.01.002 · Cited by 893
Exploiting senescence for the treatment of cancer
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Metadata
- 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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