AS04 drives superior cross-protective antibody response by increased NOTCH signaling of Dendritic Cells and proliferation of memory B cells
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PROVIDER: PRJNA1276556 | ENA |
REPOSITORIES: ENA
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Project description:The Gardasil-4® vaccine targets HPV types 6, 11, 16 and 18 and is formulated with amorphous alum. Cervarix® targets HPV types 16 and 18 using AS04 (Al(OH)3 + TLR4 agonist MPL) to enhance immune response. Cervarix elicits higher cross-protection against other high-risk HPV types, likely mediated by AS04. To investigate mechanisms of cross-neutralizing potential, six monozygotic twins (12 females aged 9-13 years) were vaccinated with either Cervarix or Gardasil-4 (2 doses, 6 months apart). Serum neutralizing antibody titers against HPV 6,16,18,31,33,45,52, and 58 were assessed pre-vaccination and 7 days post-second dose. Multi-omic single cell RNA and ATAC sequencing of PBMCs was performed at the latter timepoint. Cervarix generated higher cross-neutralizing antibody titers than Gardasil-4. Higher frequencies of dendritic cells and memory B cells were observed. Gene Set Enrichment Analysis (GSEA) indicated enhanced pathways related to NOTCH2 signaling in DCs and cell cycling/RNA translation in B cells, correlating positively with cross-neutralizing antibody titers. Increased chromatin accessability in genes related to NOTCH signaling in cDC1 was also observed. Cervarix-vaccinated subjects showed increased DC-to-memory B signaling, through upregulation of NOTCH ligands. Engagement of NOTCH was associated to BCL2 expression in memory B cells, supporting an anti-apoptotic state, and resulted in increased IgG4 expression by B memory cells. Increased DC signaling, including NOTCH, through AS04 in Cervarix supports cell survival and sustained RNA translation in memory B cells, 7 days post-vaccination. This may enhance adaptive immune cell maturation, providing a mechanism that can lead to improved cross-reactivity.
2025-07-29 | GSE299801 | GEO
Project description:The IRF8-dependent subset of classical dendritic cells (cDC), termed cDC1, is important for cross-priming cytotoxic T cell responses against pathogens and tumors. Culture of hematopoietic progenitors with DC growth factor Flt3 ligand (Flt3L) yields very few cDC1 (in humans) or only immature "cDC1-like" cells (in the mouse). We report that OP9 stromal cells expressing Notch ligand Delta-like 1 (OP9-DL1) optimize Flt3L-driven development of cDC1 from murine immortalized progenitors and primary bone marrow cells. Co-culture with OP9-DL1 induced IRF8-dependent cDC1 with the phenotype (CD103+ Dec205+ CD8α+) and expression profile resembling ex vivo cDC1. OP9-DL1-induced cDC1 showed preferential migration towards Ccr7 ligands in vitro and superior T cell cross-priming and antitumor vaccination in vivo. Co-culture with OP9-DL1 also greatly increased the yield of IRF8-dependent CD141+ cDC1 from human bone marrow progenitors cultured with Flt3L. Thus, Notch signaling optimizes cDC generation in vitro and yields authentic cDC1 for functional studies and therapeutic applications.
2018-06-05 | GSE110577 | GEO
Project description:This randomized phase I/II clinical trial is studying the side effects and best dose of gamma-secretase/notch signalling pathway inhibitor RO4929097 when given together with vismodegib and to see how well they work in treating patients with advanced or metastatic sarcoma. Vismodegib may slow the growth of tumor cells. Gamma-secretase/notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vismodegib together with gamma-secretase/notch signalling pathway inhibitor RO4929097 may be an effective treatment for sarcoma.
| 2091475 | ecrin-mdr-crc
Project description:Notch signaling promotes commitment of keratinocytes to differentiation and suppresses tumorigenesis. p63, a p53 family member, has been implicated in establishment of the keratinocyte cell fate and/or maintenance of epithelial self-renewal. Here we show that p63 expression is suppressed by Notch1 activation in both mouse and human keratinocytes through a mechanism independent of cell cycle withdrawal and requiring down-modulation of selected interferon-responsive genes, including IRF7 and/or IRF3. In turn, elevated p63 expression counteracts the ability of Notch1 to restrict growth and promote differentiation. p63 functions as a selective modulator of Notch1-dependent transcription and function, with the Hes-1 gene as one of its direct negative targets. Thus, a complex cross-talk between Notch and p63 is involved in the balance between keratinocyte self-renewal and differentiation. Keywords: Notch1, p63, keratinocyte differentiation, gene expression profiling
2006-07-08 | GSE5229 | GEO
Project description:While the acquisition of cellular plasticity in adult stem cells is essential for rapid restoration after tissue injury, little is known about the underlying molecular mechanisms governing this process. Here, we reveal that Notch signaling is a pivotal determinant conferring cross-compartment differentiation plasticity of airway secretory cells. Temporal Notch inhibition in secretory cells is required for alveolar differentiation upon injury, which is mediated by IL-1β-dependent modulation of Jag1/2 expression in ciliated cells. We also identify Fosl2/Fra2 as an essential transcription factor responsible for the regeneration of secretory cell-derived alveolar type 2 (sAT2) cells retaining distinct genetic/epigenetic features. We furthermore reveal that KDR/FLK-1+ human secretory cells display a conserved capacity to generate AT2 cells via Notch inhibition. Our results demonstrate that Notch signaling acts as a functional rheostat for fate decision of secretory cells during injury repair, proposing a new potential therapeutic target for human lung alveolar regeneration.
2021-09-08 | GSE153677 | GEO
Project description:While the acquisition of cellular plasticity in adult stem cells is essential for rapid restoration after tissue injury, little is known about the underlying molecular mechanisms governing this process. Here, we reveal that Notch signaling is a pivotal determinant conferring cross-compartment differentiation plasticity of airway secretory cells. Temporal Notch inhibition in secretory cells is required for alveolar differentiation upon injury, which is mediated by IL-1β-dependent modulation of Jag1/2 expression in ciliated cells. We also identify Fosl2/Fra2 as an essential transcription factor responsible for the regeneration of secretory cell-derived alveolar type 2 (sAT2) cells retaining distinct genetic/epigenetic signatures. We furthermore reveal that KDR/FLK-1+ human secretory cells display a conserved capacity to generate AT2 cells via Notch inhibition. Our results demonstrate that Notch signaling acts as a functional rheostat for fate decision of secretory cells during injury repair, proposing a new potential therapeutic target for human lung alveolar regeneration.
2021-09-08 | GSE154218 | GEO
Project description:Loss or damage to the mandible due to trauma, treatment of oral malignancies, and other diseases is currently treated using bone grafting techniques that suffer from numerous shortcomings and contraindications. Zebrafish naturally heal large injuries to their mandibular bone, and thus offer an opportunity to understand how to boost intrinsic healing ability. Using a novel her6:mCherry Notch reporter, we show that canonical Notch signaling is induced during the initial stages of cartilage callus formation in both mesenchymal cells and chondrocytes. We also show that modulation of Notch signaling during the initial postoperative period results in lasting changes to regenerate bone quantity one month later. Notch signaling is required for mandibular bone healing, as pharmacological inhibition of Notch signaling blocks cartilage callus formation and results in non-union. Conversely, conditional transgenic activation of Notch signaling accelerates regenerative ossification. Mechanistically, we report that postoperative Notch signaling regulates multiple phases of chondroid regeneration and patterns callus metabolic landscape. Given conserved functions of Notch signaling in bone repair across vertebrates, we propose that targeted activation of Notch signaling during the early phases of bone healing may have therapeutic value.
2022-03-07 | PXD027280 | Pride
Project description:Recent studies have shown that stem cell memory T (TSCM) cell-like properties are important for the successful adoptive immune therapy by the chimeric antigen receptor-engineered-T (CAR-T) cells. We previously reported that both human and murine activated T cells are converted into stem cell memory-like T (iTSCM) cells by co-culture with stromal OP9 cells expressing the NOTCH-ligand. However, the mechanism of NOTCH-mediated iTSCM reprogramming remains to be elucidated. Here, we report that the NOTCH/OP9 system efficiently converts conventional human CAR-T cells into TSCM-like CAR-T, “CAR-iTSCM” cells, and that the mitochondrial metabolic reprogramming plays a key role in this conversion. The NOTCH signals promote mitochondrial biogenesis and fatty acid synthesis during iTSCM formation, which are essential for the properties of iTSCM cells. We identified fork head box M1 (FOXM1) as a downstream target of NOTCH, which is responsible for these metabolic changes and the subsequent iTSCM differentiation. Like NOTCH-induced CAR-iTSCM cells, FOXM1-induced CAR-iTSCM cells possess superior antitumor potential compared to conventional CAR-T cells. We propose that the NOTCH- or FOXM1-driven CAR-iTSCM formation is an effective strategy for improving cancer immunotherapy.
2019-09-04 | GSE136765 | GEO
Project description:Notch signaling facilitates in vitro generation of cross-presenting classical dendritic cells
| PRJNA434005 | ENA