EV_DNA_integration
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB83979 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Antigen processing and presentation (APP) is essential for adaptive immunosurveillance in all nucleated cells. Here we describe a novel mechanism through which secreted factors other than cytokines, specifically extracellular vesicles (EVs) released from activated T cells (ATEVs) drive a positive feedback loop that enhances antigen presentation and immune responses in normal physiology and cancer. ATEV-induced immunogenicity relies on extravesicular double-stranded DNA (EVDNA) and granzyme B (Gzmb). ATEV-DNA is notably abundant, primarily consisting of genomic DNA enriched in copies of specific genes, including numerous APP machinery genes. Mechanistically, ATEV transfer of APP machinery genes to recipient dendritic or tumor cells is facilitated by Gzmb disruption of recipient cell nuclear integrity. DNAse treatment of ATEVs removed the majority of EVDNA, preventing APP machinery upregulation in recipient cells, which in turn failed to recruit T lymphocytes into tumors. Notably, ATEVs hold promise as an immune-boosting therapeutic, particularly in restoring MHC-I antigen processing and presentation, and synergize with checkpoint blockade therapy in several immunotherapy-refractory tumors. Collectively, our findings uncover a novel mechanism through which ATEVs boost APP and anti-tumor immunity. Gzmb-mediated nuclear transfer opens new avenues for non-viral gene delivery, offering potential for enhanced intranuclear gene transport and expression efficiency.
2025-03-06 | GSE290972 | GEO
Project description:Antigen processing and presentation (APP) is essential for adaptive immunosurveillance in all nucleated cells. Here we describe a novel mechanism through which secreted factors other than cytokines, specifically extracellular vesicles (EVs) released from activated T cells (ATEVs) drive a positive feedback loop that enhances antigen presentation and immune responses in normal physiology and cancer. ATEV-induced immunogenicity relies on extravesicular double-stranded DNA (EVDNA) and granzyme B (Gzmb). ATEV-DNA is notably abundant, primarily consisting of genomic DNA enriched in copies of specific genes, including numerous APP machinery genes. Mechanistically, ATEV transfer of APP machinery genes to recipient dendritic or tumor cells is facilitated by Gzmb disruption of recipient cell nuclear integrity. DNAse treatment of ATEVs removed the majority of EVDNA, preventing APP machinery upregulation in recipient cells, which in turn failed to recruit T lymphocytes into tumors. Notably, ATEVs hold promise as an immune-boosting therapeutic, particularly in restoring MHC-I antigen processing and presentation, and synergize with checkpoint blockade therapy in several immunotherapy-refractory tumors. Collectively, our findings uncover a novel mechanism through which ATEVs boost APP and anti-tumor immunity. Gzmb-mediated nuclear transfer opens new avenues for non-viral gene delivery, offering potential for enhanced intranuclear gene transport and expression efficiency.
2026-02-10 | GSE291466 | GEO
Project description:Antigen processing and presentation (APP) is essential for adaptive immunosurveillance in all nucleated cells. Here we describe a novel mechanism through which secreted factors other than cytokines, specifically extracellular vesicles (EVs) released from activated T cells (ATEVs) drive a positive feedback loop that enhances antigen presentation and immune responses in normal physiology and cancer. ATEV-induced immunogenicity relies on extravesicular double-stranded DNA (EVDNA) and granzyme B (Gzmb). ATEV-DNA is notably abundant, primarily consisting of genomic DNA enriched in copies of specific genes, including numerous APP machinery genes. Mechanistically, ATEV transfer of APP machinery genes to recipient dendritic or tumor cells is facilitated by Gzmb disruption of recipient cell nuclear integrity. DNAse treatment of ATEVs removed the majority of EVDNA, preventing APP machinery upregulation in recipient cells, which in turn failed to recruit T lymphocytes into tumors. Notably, ATEVs hold promise as an immune-boosting therapeutic, particularly in restoring MHC-I antigen processing and presentation, and synergize with checkpoint blockade therapy in several immunotherapy-refractory tumors. Collectively, our findings uncover a novel mechanism through which ATEVs boost APP and anti-tumor immunity. Gzmb-mediated nuclear transfer opens new avenues for non-viral gene delivery, offering potential for enhanced intranuclear gene transport and expression efficiency.
2026-02-10 | GSE290812 | GEO
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
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.
2025-08-30 | GSE256056 | GEO
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.
2025-08-30 | GSE256048 | GEO
Project description:Blocking plasma cell fate enhances antigen-specific presentation by B cells to boost anti-tumor immunity
| PRJNA1222873 | ENA
Project description:Tumor mutational burden (TMB), usually representing high immunogenicity, could not always predict treatment response of immune checkpoint blockade (ICB). Here, we showed that defective antigen cross-presentation in type 1 conventional dendritic cells (cDC1) was responsible for lacking tumor-specific cytotoxic T lymphocytes (CTLs) in triple-negative breast cancer (TNBC) patients. Mechanistically, tumor cytosolic CDC37, shuttled via extracellular vesicles (EVs) into the endosomes of intratumor DCs, inhibited antigen cross-presentation by locking antigen binding to HSP90 and precluding their translocation from endosomes to cytoplasm. CDC37 knockdown in tumor cells or inhibiting CDC37/HSP90 interaction in DCs efficiently promoted antigen translocation and enhanced their cross-presentation, which improved ICB therapeutic responses. Clinically, high tumor CDC37 expression was associated with low infiltration of antigen-specific CTLs and poor ICB efficacy in TNBC patients. Therefore, tumor EV-shuttled CDC37 locks antigen/chaperone interaction and impairs antigen cross-presentation in DCs. Moreover, targeting CDC37 is promising to enhance anti-tumor immunity and reverse ICB resistance.
2025-10-17 | PXD069576 |
Project description:Dendritic cell (DC) vaccines have been proposed as cancer immunotherapies due to their role as crucial antigen-presenting cells that regulate T cell functions. Despite considerable efforts to optimize ex vivo priming of DCs, DC vaccines have rarely been successful, suggesting the presence of unknown inhibitory factors. Here, we examined DC differentiation dynamics and discovered that ALDH1a2-produced retinoic acid (RA) acts as a bottleneck factor, initiating negative feedback to inhibit DC maturation. Removing this inhibition through either genetic knockout or pharmacological blockade using KyA33, an ALDH1a2 inhibitor we developed, significantly enhances DC maturation, phagocytosis, antigen presentation, and T cell activation, in part by downregulating glucose metabolism. KyA33 demonstrates favorable drug-like properties, including low toxicity, high membrane permeability, and low cell efflux rate. Its non-covalent binding to ALDH1A2 was also validated through X-ray crystallography. Importantly, application of KyA33 generates more robust DCs vaccines, promoting anti-tumor immunity through enhancing antigen-specific T cell responses. Our investigation highlights the intricate interplay between retinoid signaling, dendritic cell maturation, and immune metabolism, offering promising avenues for enhancing cancer immunotherapies.
2025-11-03 | MTBLS10389 | MetaboLights