Phosphorylated RB Promotes Cancer Immunity by Inhibiting NF-κB Activation and PD-L1 Expression.
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ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2019-01-03
Date Accepted
2018-10-19
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.
Citation
Molecular Cell, 2019, 73 (1), pp. 22 - 35.e6
Source Title
Molecular Cell
Publisher
CELL PRESS
ISSN
1097-2765
eISSN
1097-4164
Collections
Research Team
PrCa Targeted Therapy