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Mol Cell. 2019 Jan 3;73(1):22-35.e6. doi: 10.1016/j.molcel.2018.10.034. Epub 2018 Dec 6.

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

Author information

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.

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

PMID:
30527665
DOI:
10.1016/j.molcel.2018.10.034
[Indexed for MEDLINE]

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