Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE242098 | GEO | 2023/11/30
REPOSITORIES: GEO
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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 | GSE242080 | GEO
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
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 | GSE242096 | GEO
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 | GSE242083 | GEO
Project description:PurposeAlthough gemcitabine-based chemotherapy is most recommended for pancreatic ductal adenocarcinoma (PDAC), its effectiveness is limited because of drug resistance. Given thalidomide's anti-tumor effects in solid tumors, we investigated the effect of avadomide, a novel thalidomide analog, on PDAC and explored its anti-tumor mechanisms.MethodsPDAC cell lines, including gemcitabine-resistant (GR) clones derived from MiaPaCa2 cells, were used to evaluate the effects of avadomide. An annexin V assay, a cell cycle assay, and western blot analysis were performed to explain the mechanism of avadomide as an anti-tumor reagent. Moreover, we investigated the anti-tumor effect on tumor growth using a subcutaneous xenograft murine model.ResultsAvadomide showed anti-tumor effects in human PDAC cell lines. The proportion of apoptotic cells and G0/G1 phase cells after avadomide treatment increased, especially in the GR PDAC clones. Western blot analysis also showed the induction of the apoptotic pathway by inhibiting the NF-κB process and G1 phase cell cycle arrest. The xenograft murine model revealed that the proportion of viable cells in the avadomide-treated group was lower than that in the untreated group.ConclusionOur findings suggest that avadomide could be a novel therapeutic option to overcome gemcitabine resistance in patients with PDAC.
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Project description:Introduction: The dismally slow improvement in patient survival over the years for pancreatic cancer patients is mainly due to two factors: the late diagnosis, at which point the disease is spread to distant organs; and the fact that tumor cells are surrounded by a dense, highly immunosuppressive microenvironment. The tumor microenvironment not only shields pancreatic cancer cells from chemotherapy but also leaves it unsusceptible to various immunotherapeutic strategies that have been proven successful in other types of cancer. Areas covered: This review highlights the main components of the pancreatic tumor microenvironment, how they cross-talk with each other to generate stroma and promote tumor growth. Additionally, we discuss the most promising treatment targets in the microenvironment whose modulation can be robustly tested in combination with standard of care chemotherapy. Currently, active clinical trials for pancreatic cancer involving components of the microenvironment are also listed. Expert opinion: Although immunotherapeutic approaches involving checkpoint inhibition are being pursued enthusiastically, there is still more work to be done with several other emerging immune targets that could provide therapeutic benefit.
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