Targeting the CD40 Co-stimulatory receptor to improve virotherapy efficacy in diffuse midline gliomas
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ABSTRACT:
PROVIDER: PRJNA1242194 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR32863036_1.fastq.gz | Fastqsanger.gz | |||
| SRR32863036_2.fastq.gz | Fastqsanger.gz | |||
| SRR32863037_1.fastq.gz | Fastqsanger.gz | |||
| SRR32863037_2.fastq.gz | Fastqsanger.gz |
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Project description:Diffuse Midline Glioma (DMG) is a devastating pediatric brain tumor. The oncolytic adenovirus Delta-24-RGD has shown promising efficacy and safety in DMG patients but is not yet curative. Thus, we hypothesized that activating dendritic cells through the CD40 costimulatory receptor could increase antigen presentation and enhance the anti-tumor effect of the virus, resulting in long-term responses. This study showed that the intratumoral co-administration of Delta-24-RGD and a CD40 agonistic antibody is well tolerated and induced long-term anti-tumor immunity, including complete responses (up to 40%) in DMG preclinical models. Mechanistic studies revealed that this therapy increased tumor proliferating T lymphocytes and proinflammatory myeloid cells, including mature dendritic cells with superior tumor antigen uptake capacity. Moreover, the lack of cross-priming DCs and the prevention of DCs recruitment into the tumor abolish the Delta-24-RGD+anti-CD40 anti-tumor effect. This approach shows potential for combining virotherapy with activating antigen-presenting cells in these challenging tumors.
2025-05-29 | GSE292938 | GEO
Project description:Abstract With a 2-year survival less than 20%, Diffuse Intrinsic Pontine Glioma (DIPG) is the principal cause of pediatric death. Despite recent advances in the current treatments, the outcome for children with DIPGs remains dismal. Since the approval of T-VEC for melanoma by the FDA, oncolytic adenoviruses have emerged as a promising therapeutic strategy for brain tumors. Thus, our group launched the first world clinical trial phase I with the oncolytic adenovirus Delta-24-RGD (DNX-2401 in the clinic) for newly diagnosed DIPG (NCT03178032), which has shown safety and feasibility. Despite DNX-2401 increases the recruitment of T cells into the tumor, they usually become inactive due to the non-responsive tumor microenvironment evidencing the urgent need to improve this strategy focusing on the generation of effective long-term immune responses. Therefore, we decided to combine the Delta-24-RGD with the targeting of the costimulatory molecule CD40 in immunocompetent mice bearing orthotopic DIPG. The activation of the CD40 receptor, which is expressed by antigen presenting cells (APC) such as microglia, macrophages, and dendritic cells, is known to increase antigen presentation and enable T-cell priming and activation. Here, we observed that in addition to Delta-24-RGD anti-tumor effects, the stimulation of CD40 (using an agonistic antibody) on the tumor APCs results in a remodeling of the tumor immune compartment towards a proinflammatory scenario and a more efficient T-cell infiltration. Of importance, the combination therapy extends survival of treated mice as compared to single treatments or non-treated mice. In addition, we observe a complete regression of tumors in more than 40% of treated mice and the development of long-term anti-tumor immunity. We believe that these results provide a translational breakthrough in the treatment of these lethal tumors and open the door for a future innovative clinical trial.
| S-EPMC9164981 | biostudies-literature
Project description:Genome wide DNA methylation profiling of an H3K27M-mutant diffuse gliomas with a non-midline location. The Illumina Infinium Human EPIC DNA methylation Beadchip was used to obtain DNA methylation profiles from more than 850,000 CpGs from a FFPE sample.
2025-05-01 | GSE262639 | GEO
Project description:Genome wide DNA methylation profiling of an H3K27M-mutant diffuse gliomas with a non-midline location. The Illumina Infinium Human EPICV2 DNA methylation Beadchip was used to obtain DNA methylation profiles across more than 935,000 CpGs from a FFPE sample.
2025-05-01 | GSE262640 | GEO
Project description:In this study, by microarray we analyzed gene expression changes due to LMP1 signaling and CD40 signaling in B cells, in order to identify similarly as well as differentially induced candidate tumor-associated antigens (TAAs) and co-stimulatory ligands.
2020-12-17 | GSE159854 | GEO
Project description:To investigate the ability for pevonedistat to sensitize renal 786-0 carcinoma cells to VSVd51 oncolyic virotherapy, we treated cells with monotherapies or combination and sequencinced the transcriptome for antiviral interferon impact
2023-09-28 | GSE206428 | GEO
Project description:Diffuse midline glioma (DMG) is a devastating disease that is defined by its localization, by the diffuse growth of astrocytic tumor cells, and by K27M mutations within Histone H3 proteins. In a large series of such tumor samples (n=83), we show here that 12 % of these cases (n=10) harbor concomitant hotspot mutations within FGFR1 or BRAF. Respective cases were all located in midline structures and matched with reference cases of DMG using global DNA methylation profiling. TP53 mutations were significantly more frequent in BRAF/FGFR1 wild type cases. Presence of hotspot mutations within FGFR1 or BRAF was associated with a significantly better overall survival, which was independent of the patients’ age and tumor localization. Thus, our results establish the relevance of FGFR1 or BRAF mutations in DMG as a prognostic marker and open new targeted therapy options in this subgroup of DMG.
2020-12-08 | GSE161944 | GEO
Project description:Atherosclerosis, the underlying vascular cause of cardiovascular disease, has a strong inflammatory component. The co-stimulatory CD40-CD40 ligand (CD40L) signaling axis is a pivotal regulator of immune responses in atherosclerosis. However, therapeutic long-term inhibition of CD40L will severely compromise the immune system making it a non-viable treatment option. To circumvent this issue, cell-specific inhibition may present a better approach to target the CD40-CD40L axis. Therefore, we generated T cell and platelet-specific knockout mice for CD40L and apolipoprotein E, which were aged for 28 weeks to study their effects on immune status and atherosclerosis. Here, we show that T cell specific deficiency in CD40L signaling reduced plaque progression through hampered Th1 polarization as well as reduced antigen-dependent proliferation and oxLDL IgM production. DC-specific CD40 deficient mice displayed a similar phenotype. Platelet-specific CD40L deficiency, however, failed to decrease atherosclerosis, but ameliorated atherothrombosis. Together, our results illuminate the divergent cell-specific mechanisms of CD40-CD40L signaling in atherosclerosis, which may lead to advances in targeted therapies.
2021-03-16 | GSE145585 | GEO
Project description:Background: The co-stimulatory CD40-CD40L dyad is an important driver of atherosclerosis. CD40 exerts divergent, cell-specific roles, which differentially impact atherogenesis. Objectives: We here investigate the role of the most prominent CD40-expressing cell-type, the B-cell, in atherosclerosis. Methods: B-cell subset specific CD40-expression of patients with mild and severe coronary artery disease (CAD) was determined by mass-cytometry and correlated to CAD severity. Underlying mechanisms were elucidated using B-cell CD40-deficient CD19Cre-CD40flfl-ApoE-/-(CD40BKO) mice and control littermates (CD40BWT). Results: Patients with severe CAD had similar CD40 expression levels on most B-cell subsets but showed a profound decrease in CD40 on putative B1 cells. This was associated with increased atherosclerotic plaque burden and decreased plaque fibrosis. Likewise, CD40BKO mice exhibited an increased plaque area and more advanced staging of atherosclerosis. Absence of CD40 on B-cells caused a decrease in immunoglobulin (Ig) producing cells, including germinal center-, plasma-, but especially B1 cells, thereby reducing levels of (anti-ox/MDA-LDL) IgG and protective (anti-ox/MDA-LDL) IgM. Transcriptomics analysis revealed that the absence of CD40 on B1b cells caused altered gene expression pathways related to lipid uptake (Cd36, Ldlr), cellular stress and metabolism (Nr4a1, Hif1a), and cell death (Naip5/6, Ccnd2). Indeed, in vitro analysis showed that B1bCD40KO cells took up excessive amounts of ac/oxLDL, exhibited defective BCR signaling, and were prone to apoptosis, especially in hyperlipidemic conditions. Transfer of wild-type B1b cells in CD40BKO mice prevented the increase in atherosclerosis. Conclusions: Patients with severe CAD had similar CD40 expression levels on most B-cell subsets but showed a profound decrease in CD40 on putative B1 cells. This was associated with increased atherosclerotic plaque burden and decreased plaque fibrosis. Likewise, CD40BKO mice exhibited an increased plaque area and more advanced staging of atherosclerosis. Absence of CD40 on B-cells caused a decrease in immunoglobulin (Ig) producing cells, including germinal center-, plasma-, but especially B1 cells, thereby reducing levels of (anti-ox/MDA-LDL) IgG and protective (anti-ox/MDA-LDL) IgM. Transcriptomics analysis revealed that the absence of CD40 on B1b cells caused altered gene expression pathways related to lipid uptake (Cd36, Ldlr), cellular stress and metabolism (Nr4a1, Hif1a), and cell death (Naip5/6, Ccnd2). Indeed, in vitro analysis showed that B1bCD40KO cells took up excessive amounts of ac/oxLDL, exhibited defective BCR signaling, and were prone to apoptosis, especially in hyperlipidemic conditions. Transfer of wild-type B1b cells in CD40BKO mice prevented the increase in atherosclerosis.
2024-10-19 | GSE186134 | GEO
Project description:We generated a syngeneic H3K27M diffuse midline glioma (DMG) mouse model and performed total RNA seq on H3K27MPP cells and control cell lines H3wtMPP and Normal Neural stem cells. Aditionally we generate a Dox Inducible Mat2A Knockdown in that human DIPG cell line DIPG04 and performed RNA sequencing on cells treated with 2ug/ml Doxycyclin and no treatment
2022-01-28 | GSE160088 | GEO