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

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 kappa B (NF-kappa B) protein p65 and that their interaction is primarily dependent on CDK4/6-mediated serine-249/threonine252 (S249/T252) phosphorylation of RB. RNA-seq analysis shows a subset of NF-kappa B 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 hyper-phosphorylated RB in suppressing NF-kappa B activity and PD-L1 expression and suggest that the RBNF-kappa B axis can be exploited to overcome cancer immune evasion triggered by conventional or targeted therapies.