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Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA
journal contributionposted on 2020-06-26, 09:46 authored by Matthew A Coelho, Sophie De Carne Trecesson, Sareena Rana, Davide Zecchin, Christopher Moore, Miriam Molina-Arcas, Philip East, Bradley Spencer-Dene, Emma Nye, Karin Barnouin, Ambrosius P Snijders, Wi S Lai, Perry J Blackshear, Julian Downward
The immunosuppressive protein PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system. The relative importance of the tumor microenvironment and cancer cell-intrinsic signaling in the regulation of PD-L1 expression remains unclear. We report that oncogenic RAS signaling can upregulate tumor cell PD-L1 expression through a mechanism involving increases in PD-L1 mRNA stability via modulation of the AU-rich element-binding protein tristetraprolin (TTP). TTP negatively regulates PD-L1 expression through AU-rich elements in the 3′ UTR of PD-L1 mRNA. MEK signaling downstream of RAS leads to phosphorylation and inhibition of TTP by the kinase MK2. In human lung and colorectal tumors, RAS pathway activation is associated with elevated PD-L1 expression. In vivo, restoration of TTP expression enhances anti-tumor immunity dependent on degradation of PD-L1 mRNA. We demonstrate that RAS can drive cell-intrinsic PD-L1 expression, thus presenting therapeutic opportunities to reverse the innately immunoresistant phenotype of RAS mutant cancers.
KRASPD-L1RASTTPimmunotherapytristetraprolinAnimalsB7-H1 AntigenCell Line, TumorColorectal NeoplasmsEpithelial CellsFemaleGene Expression Regulation, NeoplasticHumansIntracellular Signaling Peptides and ProteinsLung NeoplasmsMAP Kinase Kinase KinasesMaleMiceMice, Inbred BALB CMice, Inbred C57BLNeoplasm TransplantationProtein BindingProtein-Serine-Threonine KinasesProto-Oncogene Proteins p21(ras)RNA CleavageRNA StabilityRNA, MessengerSignal TransductionTristetraprolinTumor EscapeDownward FC001070CBHPPRTFC-ackGEP-ackCS-ack1107 ImmunologyImmunology