Genome-wide CRISPR screen to identfy immune evasion genes in pancreatic cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE180834 | GEO | 2021/07/27
REPOSITORIES: GEO
Similar Datasets
Project description:Tumor escape mechanisms for immunotherapy include deficiencies in antigen presentation, diminishing adaptive CD8+ T cell antitumor activity. Although innate NK cells are triggered by loss of MHC class I, their response is often inadequate. To increase tumor susceptibility to both innate and adaptive immune elimination, we performed parallel genome-wide CRISPR-Cas9 screens. This identified all components, RNF31, RBCK1, and SHARPIN, of the linear ubiquitination chain assembly complex (LUBAC). Genetic and pharmacologic ablation of RNF31, an E3 ubiquitin ligase, strongly sensitized melanoma, breast and colorectal cancer cells to both NK and CD8+ T cell killing. This occurred in a TNF-dependent manner, causing loss of A20 and non-canonical IKK complexes from TNF Receptor Complex I. Corroborating this preclinically, a small molecule RNF31 inhibitor sensitized human colon carcinoma organoids to TNF and greatly enhanced immune bystander killing of antigen-loss and antigen presentation machinery-deficient tumor cells. These results merit exploration of RNF31 inhibition as a clinical pharmacological opportunity for immunotherapy-refractory cancers.
2022-05-30 | PXD029489 | Pride
Project description:Activated SUMOylation is a hallmark of aggressive cancers. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionary conserved function of activated SUMOylation, which attenuates the immunogenicity of tumor cells. Activated SUMOylation allows cancer cells to evade CD8+ T-cell immunosurveillance by repressing the MHC-I antigen processing and presentation machinery (APM). While loss of the MHC-I APM is a frequent cause of resistance to cancer immunotherapies, the pharmacological inhibition of SUMOylation (SUMOi) restored the expression of the MHC-I APM and enhanced the susceptibility of tumor cells to CD8+ T-cell mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T-cells itself and thereby drives a feed-forward loop amplifying the specific anti-tumor immune response. In summary, we show that activated SUMOylation converts tumor cells into a state of immune evasion, and identify SUMOi as rational therapeutic strategy for enhancing the efficacy of cancer immunotherapies.
2022-01-15 | PXD030506 | Pride
Project description:In addition to accumulation of step-wise genetic mutations, epigenetic alterations play critical roles in the evolution of colon cancers. However, distinct mutational patterns and patient backgrounds render it challenging to distinguish driver epigenetic alterations from passenger epigenetic alterations. To address this, we combined the colon cancer organoid orthotopic transplantation approach with comprehensive epigenomic and transcriptomic analyses. We found that an in vivo environment induces epigenetic alterations with fetal intestinal features that converge on SOX17, a transcription factor that is required for endoderm development. Surprisingly, SOX17 knockout leads to tumour rejection in immunocompetent mice, but not in immunodeficient mice, by turning immune cold tumours into hot with robust infiltration of activated CD8+ T cells. Mechanistically, SOX17 suppresses Ifngr1-mediated MHC-I expression to evade CD8+ T cell-mediated tumour cell killing. At the tumour initiation, SOX17 expression is induced by APC loss, and SOX17 facilitates the production of LGR5- cells with low MHC-I expression to evade immune surveillance. Together, our result reveals that SOX17 is a master transcriptional factor that induces in vivo epigenetic reprograming of tumours, which provides fundamental understanding of how an immune evasion program is initiated at the early stages of colon cancer development.
2024-02-28 | GSE222709 | GEO
Project description:In addition to accumulation of step-wise genetic mutations, epigenetic alterations play critical roles in the evolution of colon cancers. However, distinct mutational patterns and patient backgrounds render it challenging to distinguish driver epigenetic alterations from passenger epigenetic alterations. To address this, we combined the colon cancer organoid orthotopic transplantation approach with comprehensive epigenomic and transcriptomic analyses. We found that an in vivo environment induces epigenetic alterations with fetal intestinal features that converge on SOX17, a transcription factor that is required for endoderm development. Surprisingly, SOX17 knockout leads to tumour rejection in immunocompetent mice, but not in immunodeficient mice, by turning immune cold tumours into hot with robust infiltration of activated CD8+ T cells. Mechanistically, SOX17 suppresses Ifngr1-mediated MHC-I expression to evade CD8+ T cell-mediated tumour cell killing. At the tumour initiation, SOX17 expression is induced by APC loss, and SOX17 facilitates the production of LGR5- cells with low MHC-I expression to evade immune surveillance. Together, our result reveals that SOX17 is a master transcriptional factor that induces in vivo epigenetic reprograming of tumours, which provides fundamental understanding of how an immune evasion program is initiated at the early stages of colon cancer development.
2024-02-28 | GSE245668 | GEO
Project description:In addition to accumulation of step-wise genetic mutations, epigenetic alterations play critical roles in the evolution of colon cancers. However, distinct mutational patterns and patient backgrounds render it challenging to distinguish driver epigenetic alterations from passenger epigenetic alterations. To address this, we combined the colon cancer organoid orthotopic transplantation approach with comprehensive epigenomic and transcriptomic analyses. We found that an in vivo environment induces epigenetic alterations with fetal intestinal features that converge on SOX17, a transcription factor that is required for endoderm development. Surprisingly, SOX17 knockout leads to tumour rejection in immunocompetent mice, but not in immunodeficient mice, by turning immune cold tumours into hot with robust infiltration of activated CD8+ T cells. Mechanistically, SOX17 suppresses Ifngr1-mediated MHC-I expression to evade CD8+ T cell-mediated tumour cell killing. At the tumour initiation, SOX17 expression is induced by APC loss, and SOX17 facilitates the production of LGR5- cells with low MHC-I expression to evade immune surveillance. Together, our result reveals that SOX17 is a master transcriptional factor that induces in vivo epigenetic reprograming of tumours, which provides fundamental understanding of how an immune evasion program is initiated at the early stages of colon cancer development.
2024-02-28 | GSE222710 | GEO
Project description:In addition to accumulation of step-wise genetic mutations, epigenetic alterations play critical roles in the evolution of colon cancers. However, distinct mutational patterns and patient backgrounds render it challenging to distinguish driver epigenetic alterations from passenger epigenetic alterations. To address this, we combined the colon cancer organoid orthotopic transplantation approach with comprehensive epigenomic and transcriptomic analyses. We found that an in vivo environment induces epigenetic alterations with fetal intestinal features that converge on SOX17, a transcription factor that is required for endoderm development. Surprisingly, SOX17 knockout leads to tumour rejection in immunocompetent mice, but not in immunodeficient mice, by turning immune cold tumours into hot with robust infiltration of activated CD8+ T cells. Mechanistically, SOX17 suppresses Ifngr1-mediated MHC-I expression to evade CD8+ T cell-mediated tumour cell killing. At the tumour initiation, SOX17 expression is induced by APC loss, and SOX17 facilitates the production of LGR5- cells with low MHC-I expression to evade immune surveillance. Together, our result reveals that SOX17 is a master transcriptional factor that induces in vivo epigenetic reprograming of tumours, which provides fundamental understanding of how an immune evasion program is initiated at the early stages of colon cancer development.
2024-02-28 | GSE222711 | GEO
Project description:In addition to accumulation of step-wise genetic mutations, epigenetic alterations play critical roles in the evolution of colon cancers. However, distinct mutational patterns and patient backgrounds render it challenging to distinguish driver epigenetic alterations from passenger epigenetic alterations. To address this, we combined the colon cancer organoid orthotopic transplantation approach with comprehensive epigenomic and transcriptomic analyses. We found that an in vivo environment induces epigenetic alterations with fetal intestinal features that converge on SOX17, a transcription factor that is required for endoderm development. Surprisingly, SOX17 knockout leads to tumour rejection in immunocompetent mice, but not in immunodeficient mice, by turning immune cold tumours into hot with robust infiltration of activated CD8+ T cells. Mechanistically, SOX17 suppresses Ifngr1-mediated MHC-I expression to evade CD8+ T cell-mediated tumour cell killing. At the tumour initiation, SOX17 expression is induced by APC loss, and SOX17 facilitates the production of LGR5- cells with low MHC-I expression to evade immune surveillance. Together, our result reveals that SOX17 is a master transcriptional factor that induces in vivo epigenetic reprograming of tumours, which provides fundamental understanding of how an immune evasion program is initiated at the early stages of colon cancer development.
2024-02-28 | GSE222712 | GEO
Project description:Granzyme B plays a key role in cell-mediated programmed cell death. We previously demonstrated that p53 is a functional determinant in the Granzyme B-induced cytotoxic T lymphocyte response. However, the pathways leading to activation of p53 by Granzyme B remain incompletely understood. We now demonstrate that Granzyme B induced DNA damage signaling as revealed by histone H2AX phosphorylation and subsequent activation of the stress kinase CHK2. Confocal microscopy analysis indicates that Granzyme B treatment of tumor cells induced an early translocation of endonuclease caspase-activated DNase. DNA microarray based global transcriptional profiling and RT-PCR indeed revealed genes related to DNA damage. Among these genes, hSMG-1, a genotoxic stress-activated protein, was constantly upregulated in tumor cells following Granzyme B treatment. Knockdown of the hSMG-1 gene in T1 tumor target cell line resulted in a significant inhibition of Granzyme B- and CTL-induced killing. Our data suggest that Granzyme B may exert cell death through DNA damage signaling and uncover a novel molecular link between the DNA damage pathway and Granzyme B-induced cell death.
2012-02-15 | E-TABM-1116 | biostudies-arrayexpress
Project description:Cancer cells frequently alter their lipids to grow and adapt to their environment1–3. Despite the critical functions of lipid metabolism in membrane physiology, signaling, and energy production, how specific lipids contribute to tumorigenesis is incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumor growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer (NK) and CD8+ T cells partly via interferon gamma (IFNg) signaling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNg receptor subunit 1 (Ifngr1), mediating IFNg-induced growth arrest and proinflammatory signaling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumor immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.
2024-06-26 | PXD052718 | Pride
Project description:This model describes the effects of Il-21 on tumor eradication via natural killer cell-mediated and CD8+ T-cell-mediated lysis of tumor cells. The model demonstrates changes in growth dynamics in nonimmunogenic B16 melanoma and the immunogenic MethA and MCA205 fibrosarcomas, showing a strong dependence of the NK-cell/CD8+ T-cell balance on tumor immunogenicity.
2024-09-02 | BIOMD0000000761 | BioModels