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DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion

ABSTRACT: To identify the potential signaling pathway involved in DENR KO cells upon PD-L1 production, we harvested IFNγ-treated control and DENR KO cells for RNA-seq. Bioinformatic analysis of the RNA-seq data showed that 114 genes, including PD-L1, were significantly downregulated in DENR KO cells, and multiple classical signaling pathways, including JAK-STAT, and PD-L1, were enriched.

ORGANISM(S): Mus musculus

PROVIDER: GSE183980 | GEO | 2022/02/28

REPOSITORIES: GEO

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DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion [CRISPR screen]

Project description:RNA-binding proteins (RBPs) can recognize thousands of RNAs that help to maintain cell homeostasis, and RBP dysfunction is frequently observed in various cancers. However, whether specific RBPs are involved in tumor immune evasion by regulating programmed death ligand-1 (PD-L1) is unclear. We performed targeted RBP CRISPR/Cas9 screening and identified density regulated re-initiation and release factor (DENR) as a PD-L1 regulator. DENR-depleted cancer cells exhibited reduced PD-L1 expression in vitro and in vivo. DENR depletion significantly suppressed tumor growth and enhanced the tumor-killing activity of CD8+ T cells. Mechanistically, DENR antagonized the translational repression of three consecutive upstream open reading frames (uORFs) upstream of Janus kinase 2 (JAK2); thus, DENR deficiency impaired JAK2 translation and the IFNγ-JAK-STAT signaling pathway, resulting in reduced PD-L1 expression in tumors. Overall, we discovered that the RBP DENR is a novel regulator in PD-L1 expression and highlighted the potential of DENR as a therapeutic target for immunotherapy.

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DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion

Project description:DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion

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DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion [CRISPR screen]

Project description:DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion [CRISPR screen]

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DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion.

Project description:RNA-binding proteins (RBPs) can recognize thousands of RNAs that help to maintain cell homeostasis, and RBP dysfunction is frequently observed in various cancers. However, whether specific RBPs are involved in tumor immune evasion by regulating programmed death ligand-1 (PD-L1) is unclear. Here, we perform targeted RBP CRISPR/Cas9 screening and identify density regulated re-initiation and release factor (DENR) as a PD-L1 regulator. DENR-depleted cancer cells exhibit reduced PD-L1 expression in vitro and in vivo. DENR depletion significantly suppresses tumor growth and enhances the tumor-killing activity of CD8+ T cells. Mechanistically, DENR antagonizes the translational repression of three consecutive upstream open reading frames (uORFs) upstream of Janus kinase 2 (Jak2); thus, DENR deficiency impairs JAK2 translation and the IFNγ-JAK-STAT signaling pathway, resulting in reduced PD-L1 expression in tumors. Overall, we discover an RBP DENR that could regulate PD-L1 expression for tumor immune evasion, and highlight the potential of DENR as a therapeutic target for immunotherapy.

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Polysomes from DENR knockdown cells

Project description:The aim was to identify transcripts that are poorly translated upon knockdown of DENR. Lysates from control (GFP) and DENR knockdown S2 cells were run on polysome gradients. RNA from the (80S peak + polysome peaks) was isolated and analyzed by microarrays. In parallel, total RNA from the cells was also profiled as a normalization control and profiled. The 'translation score' of translated mRNA to total RNA was then calculated for control and DENR knockdown cells. Two biological replicates for DENR knockdown and GFP knockdown were performed. For each sample, (80S+polysomes) and total RNA were profiled, leading to 8 samples in total.

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Project description:The immune checkpoint programmed death-ligand 1 (PD-L1) is expressed on the cell surface of tumor cells and is key for maintaining an immunosuppressive microenvironment through its interaction with the programmed death 1 (PD-1). Clear cell renal cell carcinoma (ccRCC) is a highly immunogenic cancer characterized by an aberrant aerobic glycolytic metabolism and is known to overexpress PD-L1. Multiple immunotherapies have been approved for the treatment of ccRCC, including cytokines and immune checkpoint inhibitors. Recently the intrinsic role of PD-L1 and interferon gamma (IFNγ) signaling have been studied in several types of tumor cells, yet it remains unclear how they affect the metabolism and signaling pathways of ccRCC. Using metabolomics, metabolic assays and RNAseq, we showed that IFNγ enhanced aerobic glycolysis and tryptophan metabolism in ccRCC cells in vitro and induced the transcriptional expression of signaling pathways related to inflammation, cell proliferation and cellular energetics. These metabolic and transcriptional effects were partially reversed following transient PD-L1 silencing. Aerobic glycolysis, as well as signaling pathways related to inflammation, were not induced by IFNγ when PD-L1 was silenced, however, tryptophan metabolism and activation of Jak2 and STAT1 were maintained. Our data demonstrate that PD-L1 expression is required to mediate some of IFNγ’s effect in ccRCC cells and highlight the importance of PD-L1 signaling in regulating the metabolism of ccRCC cells in response to inflammatory signals.

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2022-11-23 | PXD037621 | Pride

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