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KDM5A inhibits anti-tumor immune response through downregulation of antigen presentation pathway in ovarian cancer

ABSTRACT: KDM5A inhibits anti-tumor immune response through downregulation of antigen presentation pathway in ovarian cancer

PROVIDER: PRJNA800360 | ENA |

REPOSITORIES: ENA

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KDM5A inhibits anti-tumor immune response through downregulation of antigen presentation pathway in ovarian cancer [CUT&RUN]

Project description:The infiltration of effector CD8+ T cells into tumors is one of the major predictors of clinical outcome for epithelial ovarian cancer (EOC) patients. Immune cell infiltration is a complex process that could be affected by the epigenetic makeup of the tumor. Here, we demonstrate that a lysine 4 histone H3 (H3K4) demethylase KDM5A impairs immune cell infiltration and inhibits anti-tumor immune response. Mechanistically, KDM5A silences genes involved in antigen processing and presentation pathway. Antigen processing and presentation is a critical step that is required for CD8+ T cells infiltration and activation of CD8+ T cell mediated anti-tumor immune response. KDM5A inhibition restores the expression of antigen presentation pathway in vitro and promotes anti-tumor immune response mediated by CD8+ T cells in vivo in a syngeneic EOC mouse model. Notably, a negative correlation between expression of KDM5A and genes involved in antigen processing and presentation pathway such as HLA-A and HLA-B is observed in the majority of cancer types. In summary, our results establish KDM5A as a regulator of CD8+ T cells tumor infiltration and demonstrate that KDM5A inhibition is a novel therapeutic strategy aiming to boost anti-tumor immune response.

2022-05-02 | GSE194359 | GEO

KDM5A inhibits anti-tumor immune response through downregulation of antigen presentation pathway in ovarian cancer [RNA-seq]

2022-05-02 | GSE194358 | GEO

KDM5A inhibits anti-tumor immune response through downregulation of antigen presentation pathway in ovarian cancer [CUT&RUN]

Project description:KDM5A inhibits anti-tumor immune response through downregulation of antigen presentation pathway in ovarian cancer [CUT&RUN]

| PRJNA800370 | ENA

KDM5A inhibits anti-tumor immune response through downregulation of antigen presentation pathway in ovarian cancer [RNA-seq]

Project description:KDM5A inhibits anti-tumor immune response through downregulation of antigen presentation pathway in ovarian cancer [RNA-seq]

| PRJNA800371 | ENA

Oligomeric human Aβ1-42 inhibits antigen presentation

Project description:Oligomeric human Aβ1-42 inhibits antigen presentation

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KDM5A epigenetically orchestrates MHC-I associated anti-tumor immunity of immunotherapy [tumor-CUTTag]

Project description:Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Histone methylation was involved in anti-tumor immunity of ICB. However, the link between histone methylation and MHC-I regulation and the related mechanisms are poorly understood. Here we show that KDM5A, an H3K4 demethylase that is critical for MHC-I expression and associated antigen presentation capacity, induces robust immune response and enhances ICB efficacy. Mechanistically, KDM5A upregulates IFN-gamma/STAT1-mediated MHC-I expression via directly binding and suppressing Scos1 in tumor cells. The genes encoding the lysosomal cathepsins are recognized and up-regulated by KDM5A, resulting in enhanced antigen-presentation abilities of both tumor cells and dendritic cells. Furthermore, pharmacological enhancing KDM5A improves response to anti-PD-1 therapy. These investigations demonstrate that enhancing KDM5A triggers MHC-associated antigen presentation of both tumor cells and DCs simultaneously to boost antitumor immunity, thus represents a candidate ICB sensitizer.

2024-03-31 | GSE256056 | GEO

KDM5A epigenetically orchestrates MHC-I associated anti-tumor immunity of immunotherapy [DC-CUTTag]

2024-03-31 | GSE256048 | GEO

KDM5A epigenetically orchestrates MHC-I associated anti-tumor immunity of immunotherapy [DC RNA-seq]

2024-03-31 | GSE260912 | GEO

Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity [bulk RNA-seq]

Project description:Loss of antigen presentation by MHCI is a common mechanism of tumor immune evasion. Mitochondrial oxidative phosphorylation (OXPHOS) capacity influences MHCI expression, but the underlying molecular mechanisms remain unclear. Here, we demonstrate that the relative flow of electrons through complex I or II of the mitochondrial electron transport chain (ETC) regulates MHCI expression and antigen presentation in cancer cells. Specifically, reducing electron flow from complex II increases mitochondrial succinate which activates transcription of MHCI and antigen processing and presentation (APP) genes. These phenotypes are independent of the interferon (IFN) signaling pathway and driven by succinate-mediated enzymatic inhibition of lysine-specific demethylases, KDM5A/B and destabilization of polycomb repressor complex 2 (PRC2). Finally, knockout of the mitochondrial Complex I inhibitor protein, MCJ, preferentially reduces electron flow through Complex II and increases succinate which drives an enhanced antigen-dependent CD8+ T cell response to mouse melanoma tumors in vivo. These findings suggest that the mitochondrial ETC can be manipulated therapeutically to enhance antitumor immune responses independently of IFNγ.

2022-12-31 | GSE198346 | GEO

KDM5A inhibits anti-tumor immune response through downregulation of antigen presentation pathway in ovarian cancer

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

2022-04-29 | GSE194361 | GEO