LAUSR

Summary 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. Graphical Abstract Figure. No caption available. HighlightsOncogenic RAS signaling via MEK increases PD‐L1 expressionRAS regulates PD‐L1 through AU‐rich elements (AREs) in the 3′ UTR of PD‐L1 mRNAThe ARE‐binding protein tristetraprolin (TTP) negatively regulates PD‐L1 expressionRestoration of tumor cell TTP activity enhances anti‐tumor immunity &NA; Coelho et al. demonstrate a post‐transcriptional mechanism whereby oncogenic RAS signaling increases PD‐L1 expression. Mechanistically, PD‐L1 mRNA is targeted by TTP through AU‐rich elements in the 3′ UTR, making it unstable. Oncogenic RAS signaling reduces TTP activity and stabilizes the PD‐L1 transcript. Restoring TTP activity reduces PD‐L1 expression and enhances anti‐tumor immunity.