RB tumor suppressor promotes cancer immunity through downregulating PD-L1 expression

Aberrant expression of immune checkpoint protein programmed death ligand-1 (PD-L1) promotes immune tolerance in cancer. RB is a tumor suppressor known to regulate the cell cycle, DNA damage response, and differentiation. Here, we demonstrate transient knockdown or homozygous deletion of RB markedly induces PD-L1 mRNA expression. RB binds to NF?B protein p65 and serine-249/threonine-252 (S249/T252) phosphorylation of RB is important for its interaction with p65 and suppression of PD-L1 expression. RNA-seq analysis identifies a subset of NF?B pathway genes including PD-L1 are selectively upregulated by RB knockdown. S249/T252-phosphorylated RB inversely correlates with PD-L1 expression in patient samples. Expression of a RB-derived S249/T252 phospho-mimicking peptide blocks radiation-induced PD-L1 expression and increases the anti-cancer efficacy of radiation in mice. Our findings reveal a previously unappreciated tumor suppressor function of hyperphosphorylated RB in inhibition of NF?B activity and PD-L1 expression, suggesting this regulatory module can be exploited to overcome cancer immune evasion. Overall design: Examination of RNA expression in PC-3 cells knocked down endogenous RB or treated cells with the CDK4/6 inhibitor palbociclib

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Jin X, Ding D, Yan Y, Li H, Wang B, Ma L, Ye Z, Ma T, Wu Q, Rodrigues DN, Kohli M, Jimenez R, Wang L, Goodrich DW, de Bono J, Dong H, Wu H, Zhu R, Huang H