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  3. Phosphorylated RB Promotes Cancer Immunity by Inhibiting NF-κB Activation and PD-L1 Expression

Phosphorylated RB Promotes Cancer Immunity by Inhibiting NF-κB Activation and PD-L1 Expression

  • Mol Cell. 2019 Jan 3;73(1):22-35.e6. doi: 10.1016/j.molcel.2018.10.034.
Xin Jin 1,  Donglin Ding 2,  Yuqian Yan 2,  Hui Li 2,  Bo Wang 1,  Linlin Ma 3,  Zhenqing Ye 4,  Tao Ma 2,  Qiang Wu 5,  Daniel N Rodrigues 6,  Manish Kohli 7,  Rafael Jimenez 8,  Liguo Wang 4,  David W Goodrich 9,  Johann de Bono 6,  Haidong Dong 10,  Heshui Wu 11,  Runzhi Zhu 12,  Haojie Huang 13
Affiliations

Affiliations

  • 1 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • 2 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • 3 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Center for Cell Therapy, The Affiliated Hospital of Jiangsu University, Zhenjiang, China.
  • 4 Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • 5 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
  • 6 The Institute of Cancer Research, London, UK.
  • 7 Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • 8 Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • 9 Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute (RPCI), Buffalo, NY 14263, USA.
  • 10 Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • 11 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: heshuiwu@hust.edu.cn.
  • 12 Center for Cell Therapy, The Affiliated Hospital of Jiangsu University, Zhenjiang, China. Electronic address: runzhizhu1978@163.com.
  • 13 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Electronic address: huang.haojie@mayo.edu.
PMID: 30527665 DOI: 10.1016/j.molcel.2018.10.034
Abstract

Aberrant expression of programmed death ligand-1 (PD-L1) in tumor cells promotes Cancer progression by suppressing Cancer immunity. The retinoblastoma protein RB is a tumor suppressor known to regulate the cell cycle, DNA damage response, and differentiation. Here, we demonstrate that RB interacts with nuclear factor κB (NF-κB) protein p65 and that their interaction is primarily dependent on CDK4/6-mediated serine-249/threonine-252 (S249/T252) phosphorylation of RB. RNA-seq analysis shows a subset of NF-κB pathway genes including PD-L1 are selectively upregulated by RB knockdown or CDK4/6 inhibitor. S249/T252-phosphorylated RB inversely correlates with PD-L1 expression in patient samples. Expression of a RB-derived S249/T252 phosphorylation-mimetic peptide suppresses radiotherapy-induced upregulation of PD-L1 and augments therapeutic efficacy of radiation in vivo. Our findings reveal a previously unrecognized tumor suppressor function of hyperphosphorylated RB in suppressing NF-κB activity and PD-L1 expression and suggest that the RB-NF-κB axis can be exploited to overcome Cancer immune evasion triggered by conventional or targeted therapies.

Keywords

CDK4/6 inhibitor; CHD1; MAP3K7; NF-κB; PD-L1; RB; immunotherapy; phosphorylation; prostate cancer; radiotherapy.

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