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. Epub 2018 Dec 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / pharmacology
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism*
  • Chemoradiotherapy / methods
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / metabolism
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • PC-3 Cells
  • Phosphorylation
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / therapy
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Radiation Tolerance
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / immunology
  • Retinoblastoma Protein / metabolism*
  • Signal Transduction
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / immunology
  • Transcription Factor RelA / metabolism*
  • Tumor Escape*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • CD274 protein, human
  • RELA protein, human
  • Retinoblastoma Protein
  • Transcription Factor RelA
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6