Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma [ATAC-seq]
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. Overall design: To investigate the function of Med12 regulating tumor instrinsic immunogenicity, wo conducted Med12 KO and WT cell lines. Then, we performed ATAC-seq sequencing to combine with RNAseq to  analyse how Med12 regulates retroelements inhibition.