Abstract
MYC and KRASG12D exhibit distinct roles in the post-transcriptional regulation of immune checkpoints.
Major finding: MYC and KRASG12D exhibit distinct roles in the post-transcriptional regulation of immune checkpoints.
Concept: MYC drives eIF2-driven bypass of KRASG12D-mediated suppression of the translation of PD-L1.
Impact: Clinically targeting translational control may enhance the efficacy of immunotherapy.
Oncogenes promote tumorigenesis by driving tumor growth and transcriptionally regulating the expression of immune checkpoints to promote immune escape, but it is unclear whether oncogenes also post-transcriptionally regulate immune checkpoint expression. To ascertain how oncogenes cooperate to control immune checkpoint expression, Xu, Poggio, and colleagues generated genetic mouse models of hepatocellular carcinoma with liver-targeted MYC overexpression (MycTg) and/or expression of KrasG12D. Only MycTg;KrasG12D mice developed aggressive, highly metastatic and inflamed tumors: KrasG12D mice developed tumors that were less inflamed and metastatic, and MycTg mice failed to develop liver tumors. MycTg;KrasG12D tumors were found to be transcriptionally, but not translationally, similar to KrasG12D tumors, although there was no difference in global protein synthesis rates. Further, although both MycTg;KrasG12D and KrasG12D tumors exhibited increased expression of Cd274 (the mouse ortholog of PD-L1), only MycTg;KrasG12D tumors exhibited upregulation of PD-L1 ribosome footprints and expression of PD-L1 protein. Ribosomes in KrasG12D tumors translate two upstream open reading frames (uORF) with uAUG and uCUG start sites, respectively, in the PD-L1 5′-UTR and do not translate the main PD-L1 ORF, suggesting that these uORFs prevent PD-L1 protein translation, while ribosomes engage the canonical AUG start site and synthetize PD-L1 in MycTg;KrasG12D tumors. Mutation of uAUG or uCUG resulted in increased luciferase reporter activity, and CRISPR/Cas9-mediated editing of uAUG or uCUG in KrasG12D tumor–derived cell lines resulted in increased PD-L1 protein levels in vitro and increased metastasis in vivo. MycTg;KrasG12D tumors exhibited increased phosphorylation of eIF2α, a component of the eIF2 translation initiation complex, that allows ribosomes to bypass the uORF translational barrier resulting in PD-L1 protein expression. Treating MycTg;KrasG12D tumors in vivo with eFT508, a new clinical compound that targets the phosphorylation of the major cap binding protein, eIF4E, decreased PD-L1 translation, increased immune activity, and decreased tumor burden. These findings characterize the post-transcriptional role of oncogenes in immunosurveillance and identify a potential immunotherapy strategy.
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