Phosphorylated RB promotes cancer immunity by inhibiting NFκB activation and PD-L1 expression. Jin et al
Description
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 RB interacts with nuclear factor κB (NFκB) protein p65 and 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 NFκB 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-mimicking peptide suppresses radiotherapy-induced upregulation of PD-L1 and markedly increases the anti-cancer efficacy of radiation in vivo. Our findings reveal a previously unrecognized tumor suppressor function of hyperphosphorylated RB in suppressing NFκB activity and PD-L1 expression and suggest that the RB-NFκB axis can be exploited to overcome conventional or targeted therapy-triggered cancer immune evasion.