Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance

Zhang, Jinfang; Bu, Xia; Wang, Haizhen; Zhu, Yasheng; Geng, Yan; Nihira, Naoe Taira; Tan, Yuyong; Ci, Yanpeng; Wu, Fei; Dai, Xiangpeng; Guo, Jianping; Huang, Yuhan; Fan, Caoqi; Ren, Shancheng; Sun, Yinghao; Freeman, Gordon J.; Siciński, Piotr

doi:10.1038/nature25015

Cited by 744 publications

(760 citation statements)

References 41 publications

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“…In support of our hypothesis, depletion of c-MYC markedly abrogated the upregulation of both PD-L1 mRNA and protein in FBXW7-knocked down cells (Figs. 22 Consistent with this notion, we were also able to detect relatively lower intensity of polyubiquitinated PD-L1 signals in the cells treated with siC-ullin3 (Fig. Consistent with the results in U87 cells, similar effect of c-MYC silencing on FBXW7 knockdown-induced PD-L1 mRNA and protein upregulation was observed in T98G cells (Figs.…”

Section: Cullin1-fbxw7/c-myc Axis Mainly Contributes To the Pd-l1 Indsupporting

confidence: 88%

“…1a and Fig. 22 Interestingly, the mRNA of PD-L1 was upregulated after cells were depleted of neddylation enzymes, indicating inhibition of neddylation pathway also transcriptionally increases PD-L1 levels ( Fig. Mature PD-L1 expressed at the surface of cancer cells exerts immunosuppressive effects by binding to PD-1 glycoprotein receptor on activated T cells.…”

Section: Genetic or Pharmacological Inhibition Of Neddylation Pathwaymentioning

confidence: 94%

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Neddylation inhibition upregulates PD‐L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma

Zhou

Zhao

Yang

et al. 2019

Intl Journal of Cancer

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Pevonedistat (MLN4924), a specific NEDD8‐activating enzyme inhibitor, has been considered as a promising treatment for glioblastoma, which is currently in Phase I/II clinical trials. On the other hand, inhibition of neddylation pathway substantially upregulates the expression of T cell negative regulator programmed death‐ligand 1 (PD‐L1), which might account for the potential resistance via evasion of immune surveillance checkpoints. Whether administration of anti‐PD‐L1 enhances the efficacy of pevonedistat through a cytotoxic T cell‐dependent mechanism in glioblastoma needs to be investigated. Here, we report that depletion of neddylation pathway key enzymes markedly elevates PD‐L1 expression in glioblastoma cancer cells. Consistently, neddylation inhibitor pevonedistat significantly enhances PD‐L1 expression in both glioblastoma cancer cell lines and animal models. Mechanistically, pevonedistat increases PD‐L1 mRNA levels mainly through inhibiting Cullin1‐F‐box and WD repeat domain‐containing 7 E3 ligase activity and accumulating c‐MYC proteins, a direct transcriptional activator of PD‐L1 gene expression. In addition, inhibition of Cullin3 activity by pevonedistat also blocks PD‐L1 protein degradation. Importantly, pevonedistat attenuates T cell killing through PD‐L1 induction, and blockade of PD‐L1 restores the sensitivity of pevonedistat‐treated glioblastoma cancer cells to T cell killing. The combination of pevonedistat and anti‐PD‐L1 therapy compared to each agent alone significantly increased the therapeutic efficacy in vivo. Our study demonstrates inhibition of neddylation pathway suppresses cancer‐associated immunity and provides solid evidence to support the combination of pevonedistat and PD‐L1/programmed cell death protein 1 immune checkpoint blockade as a potential therapeutic strategy to treat glioblastoma.

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Section: Cullin1-fbxw7/c-myc Axis Mainly Contributes To the Pd-l1 Indsupporting

confidence: 88%

Section: Genetic or Pharmacological Inhibition Of Neddylation Pathwaymentioning

confidence: 94%

Neddylation inhibition upregulates PD‐L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma

Zhou

Zhao

Yang

et al. 2019

Intl Journal of Cancer

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“…70 In a separate study, it was demonstrated that systemic CDK4/6 inhibition resulted in suppression of regulatory T cells, but had a lesser effect on CD8+ T cells, suggesting there may be an enhanced T cellmediated antitumor response. A recent study reported that CDK4/6 inhibitors enhanced PD-L1 expression on tumor cells and augmented responsiveness to PD-L1 immune therapy.…”

Section: Ddpcr Detection Of Esr1 Mutations In Patient Biopsiesmentioning

confidence: 99%

ESR1 mutations in breast cancer

Dustin

Fuqua

2019

Cancer

192

131

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The acquisition of ligand-independent ESR1 mutations during aromatase inhibitor therapy in metastatic estrogen receptor (ER)-positive breast cancer is a common mechanism of hormonal therapy resistance. Preclinical and clinical studies have demonstrated that ESR1 mutations can preexist in primary tumors and can be enriched during metastasis. Furthermore, ESR1 mutations express a unique transcriptional profile that favors tumor progression, suggesting that selected ESR1 mutations may influence metastasis. Several groups have used sensitive detection methods using patient liquid biopsies to track ESR1 or truncal somatic mutations to predict treatment outcome and tumor progression, and some of these techniques may eventually be used to guide sequential treatment options in patients. Further development and standardization of mutation tracking in circulating tumor DNA is ongoing. Clinically, patients with ESR1 mutations derive clinical benefit when treated with fulvestrant and CDK4/6-targeted therapies, but the development of more potent selective ER degraders and/or new targeted biotherapies are needed to overcome the endocrineresistant phenotype of ESR1 mutant-bearing tumors. In this review, we discuss the mechanisms of resistance and dissemination of ESR1 mutations as well as the detection methods for ESR1 mutation tracking, newly discovered potential therapeutic targets, and the clinical implications and treatment options for treating patients with ESR1 mutant-bearing tumors.

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“…[39] Recent breakthroughs in cancer immunotherapy, like discovering immune checkpoints and engineering chimeric antigen receptor (CAR)-T cells, [40] have reinvigorated the field of oncology. There have been century-long efforts to harness immune systems for human health, and vaccination has been a standard healthcare method in the last few decades.…”

Section: Immune Cell Engineering For Cancer Therapymentioning

confidence: 99%

Engineering Precision Medicine

et al. 2018

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Advances in genomic sequencing and bioinformatics have led to the prospect of precision medicine where therapeutics can be advised by the genetic background of individuals. For example, mapping cancer genomics has revealed numerous genes that affect the therapeutic outcome of a drug. Through materials and cell engineering, many opportunities exist for engineers to contribute to precision medicine, such as engineering biosensors for diagnosis and health status monitoring, developing smart formulations for the controlled release of drugs, programming immune cells for targeted cancer therapy, differentiating pluripotent stem cells into desired lineages, fabricating bioscaffolds that support cell growth, or constructing “organs‐on‐chips” that can screen the effects of drugs. Collective engineering efforts will help transform precision medicine into a more personalized and effective healthcare approach. As continuous progress is made in engineering techniques, more tools will be available to fully realize precision medicine's potential.

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Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance

Cited by 744 publications

References 41 publications

Neddylation inhibition upregulates PD‐L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma

Neddylation inhibition upregulates PD‐L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma

ESR1 mutations in breast cancer

Engineering Precision Medicine

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