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Cyclin D–CDK4 kinase destabilizes PD-L1 via Cul3SPOP to control cancer immune surveillance

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Abstract

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 benefit1,2. However, many cancer patients fail to respond to anti-PD-1/PD-L1 treatment, and the underlying mechanism(s) is not well understood3–5. Recent studies revealed that response to PD-1/PD-L1 blockade might correlate with PD-L1 expression levels in tumor cells6,7. 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. Here, we report that PD-L1 protein abundance is regulated by cyclin D-CDK4 and the Cullin 3SPOP E3 ligase via proteasome-mediated degradation. Inhibition of CDK4/6 in vivo elevates PD-L1 protein levels, largely by inhibiting cyclin D–CDK4-mediated phosphorylation of SPOP and thereby promoting SPOP degradation by APC/CCdh1. 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 inhibitor 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.

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Author information

Author notes

    • Jinfang Zhang
    • , Xia Bu
    •  & Haizhen Wang

    These authors contributed equally to this study.

    • Gordon J. Freeman
    • , Piotr Sicinski
    •  & Wenyi Wei

    These authors jointly supervised this work.

Affiliations

  1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA

    • Jinfang Zhang
    • , Naoe Taira Nihira
    • , Yuyong Tan
    • , Yanpeng Ci
    • , Fei Wu
    • , Xiangpeng Dai
    • , Jianping Guo
    • , Yu-Han Huang
    •  & Wenyi Wei
  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA

    • Xia Bu
    •  & Gordon J. Freeman
  3. Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA

    • Haizhen Wang
    • , Yan Geng
    • , Caoqi Fan
    •  & Piotr Sicinski
  4. Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China

    • Yasheng Zhu
    • , Shancheng Ren
    •  & Yinghao Sun
  5. Department of Gastroenterology, the Second Xiangya Hospital of Central South University, Changsha 410011, P.R. China

    • Yuyong Tan
  6. School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, P.R. China

    • Yanpeng Ci
  7. Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China

    • Fei Wu
  8. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, Peking University, Beijing 100871, P.R. China

    • Caoqi Fan

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Corresponding authors

Correspondence to Gordon J. Freeman or Piotr Sicinski or Wenyi Wei.

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    This file contains the source data for gels in Figures 1–4 and Extended Data Figures 1–9.

  2. 2.

    Life Sciences Reporting Summary

  3. 3.

    Gating strategy

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