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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE256056 | GEO | 2024/03/31

REPOSITORIES: GEO

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

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 | GSE260912 | GEO

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

2024-03-31 | GSE256048 | GEO

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

Compound screen identifies inhibitor of apoptosis proteins (IAP) antagonist as an inducer of T cell proliferation after cross-presentation by dendritic cells (Mouse)

Project description:Cross-presentation of tumor antigens by dendritic cells (DCs) is crucial to prime and (re-) stimulate CD8+ T cells. This process is important in initiating and maintaining an anti-tumor response. Here, we show that tumor presence of conventional type 1 DCs (cDC1), a subtype that excels in cross-presentation, correlates with response to neoadjuvant immune checkpoint blockade (ICB) in melanoma. This led us to hypothesize that patients failing to respond to ICB could benefit from enhanced cross-presentation of tumor antigens. We therefore established a cross-presentation assay to screen over 5,500 compounds for enhancers of DC cross-presentation using induced T cell proliferation as readout. We identified 145 enhancers, including AZD5582, an antagonist of inhibitor of apoptosis proteins (IAPs) cIAP1, cIAP2 and XIAP. AZD5582 treatment led to DC activation of the non-canonical nuclear factor kappa B (NF-kB) pathway, enhanced antigen import from endolysosomes into the cytosol and increased expression of genes involved in cross-presentation. Furthermore, it upregulated expression of CD80, CD86, MHC class II, CD70 and secretion of TNF by DCs. This enhanced DC activation and maturation program was observed also in tumor-bearing mice upon AZD5582 treatment, culminating into an increased frequency of systemic tumor antigen-specific CD8+ T cells. Our results merit further exploration of AZD5582 to increase antigen cross-presentation for improving the clinical benefit of ICB in unfavorable patients.

2023-03-23 | GSE217048 | GEO

Compound screen identifies inhibitor of apoptosis proteins (IAP) antagonist as an inducer of T cell proliferation after cross-presentation by dendritic cells (Human)

2023-03-23 | GSE217050 | GEO

Transcription profiling of mouse dendritic subsets in vivo

Project description:Dendritic cells (DCs) process and present self and foreign antigens to induce tolerance or immunity. In vitro models suggest that induction of immunity is controlled by regulating the presentation of antigen, but little is known about how DCs control antigen presentation in vivo. To examine antigen processing and presentation in vivo we specifically targeted antigens to the two major subsets of DCs using chimeric monoclonal antibodies. Unlike CD8+ DCs that express the cell surface protein CD205, CD8- DCs, which are positive for the 33D1 antigen, are specialized for presentation on MHC class II. This difference in antigen processing is intrinsic to the DC subsets and associated with increased expression of proteins associated with MHC processing. Experiment Overall Design: This study includes data from cell sort purified dendritic cells, B cells and CD4 and CD8 T cells. The genearray was performed to identify the transmembrane molecule recognized by the antibody 33D1. The antibody 33D1 binds specifically to CD8-CD11cHigh DCs in the spleen. Therfore the data set was reduced in this way that all molecules that are expressed either in CD8=CD11cHigh DCs, B cells and T cells were diminished of the CD8+CD11cHigh DC data set. This Genearray was also used to analyze MHC class I and MHC class II associated moelcules as the DC subsets differ in the antigen presentation. Each Series consists of 3 individuall samples

2008-06-14 | E-GEOD-6259 | biostudies-arrayexpress

Differential antigen processing by dendritic cell subsets in vivo

2006-12-01 | GSE6259 | GEO

Induction of senescence renders cancer cells highly immunogenic

Project description:Cellular senescence is a stress response that activates innate immunity. However, the interplay between senescent cells and the adaptive immune system remains largely unexplored. Here, we show that senescent cells display enhanced MHC class I (MHC-I) antigen processing and presentation. Immunization of mice with senescent syngeneic fibroblasts generates CD8 T cells reactive against both normal and senescent fibroblasts, some of them targeting senescence-associated MHC-I-peptides. In the context of cancer, we demonstrate that senescent cancer cells trigger strong anti-tumor protection mediated by antigen-presenting cells and CD8 T cells. This response is superior to the protection elicited by cells undergoing immunogenic cell death. Finally, induction of senescence in patient-derived cancer cells exacerbates the activation of autologous tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs) with no effect on non-reactive TILs. Our study indicates that immunization with senescent cancer cells strongly activates anti-tumor immunity, and this can be exploited for cancer therapy.

2022-11-09 | PXD034059 | Pride

Mal2 drives immune evasion by reducing antigen presentation on tumor cells

Project description:Current cancer immunotherapies are assumed to improve infiltration and cytotoxicity of immune cells in the tumor. However, tumor cells have developed a variety of resistance mechanisms to suppress the MHC class I antigen presentation, and thereby impair the cytotoxicity of CD8+ T cells. Here, we identified Mal2 as a key player that mediates the turnover of the antigen-MHC-I complex and reduce the antigen presentation on tumor cells. Mal2 promotes the endocytosis of tumor antigen via direct interaction with the MHC-I complex and endosome-associated Rab5/7. In mouse and human breast tumor models, inhibition of Mal2 profoundly enhanced the cytotoxicity of tumor-infiltrating CD8+ T cells and suppressed breast tumor growth, suggesting that Mal2 is a potential target for breast cancer immunotherapy.

2020-01-23 | GSE144099 | GEO

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