Dataset Information

Targeted delivery of tumor necrosis factor in combination with lomustine induces a T-cell dependent regression of glioblastoma

ABSTRACT: Glioblastoma is the most aggressive primary brain tumor with an unmet need for more effective therapies. Here we report that the combination of L19TNF, an antibody-cytokine fusion protein based on tumor necrosis factor that selectively localizes on the tumor neo-vasculature, with the alkylating agent lomustine, can induce tumor regression in orthotopic glioma-bearing mice and patients with recurrent glioblastoma. Mechanistically, this striking synergy crucially depended on T cells and involved activation of the tumor endothelium, tumor DNA damage, treatment-associated tumor necrosis, increased antigen presentation on MHC class I and tumor immune cell infiltration, as well as decreased tumor-associated immunosuppression. The clinical translation of this approach is ongoing, but already shows durable responses in the first recurrent glioblastoma patient cohort treated with L19TNF in combination with lomustine (NCT04573192).

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Permanent Cell Line Cell, Epithelial Cell

DISEASE(S): Brain Cancer

SUBMITTER: Marcel Bühler

LAB HEAD: Tobias Weiss

PROVIDER: PXD041234 | Pride | 2026-02-23

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20210830_002_TumorCells_Pool_QC_1_S312814.d.zip	Other
	20210830_003_ICK_TumorCells_CCNUL19_5_S312797.d.zip	Other
	20210830_004_EndoCells_LibraryPool_3_S312809.d.zip	Other
	20210830_005_ICK_TumorCells_L19_5_S312780.d.zip	Other
	20210830_006_ICK_EndoCells_CCNU_1_S312798.d.zip	Other

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Publications

Understanding MeJA induced-resistance to Phytophthora cinnamomi in holm oak embryogenic lines.

Morcillo Marian M Sanchez-Lucas Rosa R Sales Ester E Jorrín-Novo Jesús J Miedes Eva E Arrillaga Isabel I

Frontiers in plant science 20260202

Holm oak (Quercus ilex L.) decline in Mediterranean forests is mostly driven by the synergistic effects of drought and Phytophthora cinnamomi, yet effective protection strategies remain elusive. Previously, we reported that elicitation of holm oak embryogenic lines with 50 µM methyl jasmonate (MeJA), did not impair somatic embryo growth and development while inducing jasmonic acid (JA) and phenolic compounds accumulation, also resulting in increased H2O2 level ...[more]

PMID: 41704790

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Project description:Background: Newer 3D culturing approaches are a promising way to better mimic the in vivo tumor microenvironment and to study the interactions between the heterogeneous cell populations of glioblastoma multiforme. Like many other tumors, glioblastoma uses extracellular vesicles as an intercellular communication system to prepare surrounding tissue for invasive tumor growth. However, little is known about the effects of 3D culture on extracellular vesicles. The aim of this study was to comprehensively characterise extracellular vesicles in 3D organoid models and compare them to conventional 2D cell culture systems.Methods: Primary glioblastoma cells were cultured as 2D and 3D organoid models. Extracellular vesicles were obtained by precipitation and immunoaffinity, with the latter allowing targeted isolation of the CD9/CD63/CD81 vesicle subpopulation. Comprehensive vesicle characterisation was performed and miRNA expression profiles were generated by smallRNA-sequencing. In silico analysis of differentially regulated miRNAs was performed to identify mRNA targets and corresponding signaling pathways. The tumor cell media and extracellular vesicle proteome were analysed by high-resolution mass spectrometry.Results: We observed an increased concentration of extracellular vesicles in 3D organoid cultures. Differential gene expression analysis further revealed the regulation of twelve miRNAs in 3D tumor organoid cultures (with nine miRNAs down and three miRNAs upregulated). MiR-23a-3p, known to be involved in glioblastoma invasion, was significantly increased in 3D. MiR-7-5p, which counteracts glioblastoma malignancy, was significantly decreased. Moreover, we identified four miRNAs (miR- 323a-3p, miR-382-5p, miR-370-3p, miR-134-5p) located within the DLK1-DIO3 domain, a cancer associated genomic region, suggesting a possible importance of this region in glioblastoma progression. Overrepresentation analysis identified alterations of extracellular vesicle cargo in 3D organoids, including representation of several miRNA targets and proteins primarily implicated in the immune response.Conclusion: Our results show that 3D glioblastoma organoid models secrete extracellular vesicles with an altered cargo compared to corresponding conventional 2D cultures. Extracellular vesicles from 3D cultures were found to contain signaling molecules associated with the immune regulatory signaling pathways and as such could potentially change the surrounding microenvironment towards tumor progression and immunosuppressive conditions. These findings suggest the use of 3D glioblastoma models for further clinical biomarker studies as well as investigation of new therapeutic options.

Dataset Information

Targeted delivery of tumor necrosis factor in combination with lomustine induces a T-cell dependent regression of glioblastoma

Dataset's files

Publications

Understanding MeJA induced-resistance to <i>Phytophthora cinnamomi</i> in holm oak embryogenic lines.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Targeted delivery of tumor necrosis factor in combination with lomustine induces a T-cell dependent regression of glioblastoma

Dataset's files

Publications

Understanding MeJA induced-resistance to &lt;i&gt;Phytophthora cinnamomi&lt;/i&gt; in holm oak embryogenic lines.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Understanding MeJA induced-resistance to <i>Phytophthora cinnamomi</i> in holm oak embryogenic lines.