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Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma

ABSTRACT: Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma

PROVIDER: PRJNA1011322 | ENA |

REPOSITORIES: ENA

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Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma [CUT&Tag]

Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, including checkpoint blockade (ICB) immunotherapy. Epigenetic dysregulation is a defining feature of tumorigenesis and contributes to immune escape. However, little is known about whether and how epigenetic regulators evade immune surveillance in PDAC. Here, we identified Med12, a subunit of RNA polymerase II, as a mediator of immune escape in PDAC with in vivo CRISPR-Cas9 Screening. In murine PDAC models, Med12 loss effectively promoted infiltration and cytotoxicity of CD8+ T cells and NK cells，thereby sensitized to ICB and led to a marked extension of survival. Mechanistically, Med12 loss derepressed endogenous retroelements via impairing H3K9me3 and increasing H3K27Ac modification, triggering cytosolic RNA-sensing and DNA-sensing pathways as well as the type I interferon pathways. Moreover, Med12 depletion induced H3K27Ac gain in the Med12-binding domains, further enhanced the interferon-related genes transcription. Our results demonstrated the role of Med12 in suppressing tumor-intrinsic immunogenicity, thus provided a potential target or marker for immunotherapy of PDAC.

2023-11-30 | GSE242097 | GEO

Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma [ATAC-seq]

2023-11-30 | GSE242080 | GEO

Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma [mouse RNA-seq]

2023-11-30 | GSE242096 | GEO

Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma [human RNA-seq]

2023-11-30 | GSE242083 | GEO

Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma [ATAC-seq]

Project description:Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma [ATAC-seq]

| PRJNA1011304 | ENA

Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma [CUT&Tag]

Project description:Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma [CUT&Tag]

| PRJNA1011325 | ENA

Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma [human RNA-seq]

Project description:Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma [human RNA-seq]

| PRJNA1011306 | ENA

Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma [mouse RNA-seq]

Project description:Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma [mouse RNA-seq]

| PRJNA1011324 | ENA

Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-11-30 | GSE242098 | GEO

Inhibiting tumor cell-intrinsic UBA6 by inosine augments tumor immunogenicity

Project description:Metabolic alteration influences cancer immunity. However, the role and mechanism of metabolic adaption on immune checkpoint blockade (ICB) responses remains ill-defined. Here, metabolomic profiling in mouse tumor models and cancer patients treated with ICB was performed. We found that metabolite inosine was associated with ICB sensitivity in mice and humans, and overcame ICB resistance in several mouse tumor models. Notably, inosine sensitized tumor cells to T cell-mediated cytotoxicity by amplifying tumor-intrinsic immunogenicity. Chemical proteomics further identified that inosine directly bound and inhibited ubiquitin-activating enzyme UBA6. Tumor intrinsic UBA6 loss augmented tumor immunogenicity and substituted the synergistic effect of inosine in combination with ICB. Clinically, tumor UBA6 expression negatively correlated with ICB response in cancer patients. Thus, we reveal an unappreciated function of inosine on tumor-intrinsic immunogenicity and UBA6 as a candidate target for immunotherapy.

2022-08-04 | GSE210225 | GEO

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