DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion
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ABSTRACT:
PROVIDER: PRJNA762565 | ENA |
REPOSITORIES: ENA
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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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Project description: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.
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Project description:DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion [CRISPR screen]
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Project description:A tumor specific super-enhancer drives immune evasion by guiding synchronous expression of PD-L1 and PD-L2
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Project description:Although genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 relieves endogenous DNA damage and suppresses cGAS-STING-dependent immune signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a transcriptional regulatory element in the PD-L1 gene, thereby promoting PD-L1 expression in cancer cells. Loss of SMARCAL1 enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a valuable target for cancer immunotherapy.
2024-01-24 | PXD046384 | Pride
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:Programmed death-ligand 1 (PD-L1), a critical immune checkpoint ligand, is a transmembrane protein synthesized in the endoplasmic reticulum of tumor cells and transported to the plasma membrane to interact with programmed death 1 (PD-1) expressed on T cell surface. This interaction delivers co-inhibitory signals to T cells, thereby suppressing their function and evading antitumor immunity. Most companion or complementary diagnostic devices for PD-L1 expression levels in tumor cells used in the clinic or clinical trials require membranous staining. However, the mechanism driving PD-L1 translocation to the plasma membrane after de novo synthesis is poorly understood. Herein, we showed that mind bomb homolog 2 (MIB2) is required for PD-L1 transportation from the trans-Golgi network (TGN) to the plasma membrane of cancer cells. MIB2 deficiency leaded to fewer PD-L1 proteins on the tumor cell surface and promotes antitumor immunity in mice.We performed a single-cell RNA sequencing (scRNA-seq) of B16-F10 tumors from C57BL/6 syngeneic mice. Knockdown of MIB2 resulted in an increase in the percentage of CD8+ CTLs (approximately 5-fold) and CD4+/CD8+ effector/activated T cells (approximately 2-fold), indicating that MIB2 downregulation enhanced the antitumor immune activity centered on CD8+ CTLs and changed their transcriptional profile. Our findings demonstrate that non-proteolytic ubiquitination of PD-L1 by MIB2 is required for its transportation to the plasma membrane and tumor cells' immune evasion.
2023-12-31 | GSE218906 | GEO
Project description:Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 relieves endogenous DNA damage and suppresses cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a transcriptional regulatory element in the PD-L1 gene, thereby promoting PD-L1 expression in cancer cells. SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a promising target for cancer immunotherapy.
2024-01-22 | GSE245449 | GEO
Project description:Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 relieves endogenous DNA damage and suppresses cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a transcriptional regulatory element in the PD-L1 gene, thereby promoting PD-L1 expression in cancer cells. SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a promising target for cancer immunotherapy.
2024-01-22 | GSE245448 | GEO
Project description:Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 relieves endogenous DNA damage and suppresses cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a transcriptional regulatory element in the PD-L1 gene, thereby promoting PD-L1 expression in cancer cells. SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a promising target for cancer immunotherapy.
2024-01-22 | GSE245447 | GEO