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Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting behavior

ABSTRACT: Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation. In contrast to the extensive datasets available on tumor cells, limited information exists on their tumor microenvironment (TME), including the immune infiltrate. Here, we characterize the TME of H3.3K27M and G34R/V-mutant gliomas, and multiple H3.3K27M mouse models, using transcriptomic and proteomic, including spatial single-cell approaches. Resolution of immune lineages indicates uniform high-infiltration of H3-mutant gliomas with diverse myeloid populations, high-level expression of immune checkpoints, and scarce lymphoid cells, findings uniformly reproduced in all H3.3K27M models tested. We show these myeloid populations communicate with H3-mutant cells mediating immunosuppression and sustaining tumor formation and maintenance. Dual inhibition of myeloid cells and immune checkpoints showed significant therapeutic benefit in pre-clinical syngeneic models. Our findings provide valuable characterization of the TME of oncohistone-mutant gliomas, and insights into means to modulate the myeloid infiltrate for the benefit of patients.

PROVIDER: EGAS00001007510 | EGA |

REPOSITORIES: EGA

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Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting behavior

Project description:Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation. In contrast to the extensive datasets available on tumor cells, limited information exists on their tumor microenvironment (TME), including the immune infiltrate. Here, we characterize the TME of H3.3K27M and G34R/V-mutant gliomas, and multiple H3.3K27M mouse models, using transcriptomic and proteomic, including spatial single-cell approaches. Resolution of immune lineages indicates uniform high-infiltration of H3-mutant gliomas with diverse myeloid populations, high-level expression of immune checkpoints, and scarce lymphoid cells, findings uniformly reproduced in all H3.3K27M models tested. We show these myeloid populations communicate with H3-mutant cells mediating immunosuppression and sustaining tumor formation and maintenance. Dual inhibition of myeloid cells and immune checkpoints showed significant therapeutic benefit in pre-clinical syngeneic models. Our findings provide valuable characterization of the TME of oncohistone-mutant gliomas, and insights into means to modulate the myeloid infiltrate for the benefit of patients.

2024-07-02 | GSE241985 | GEO

Tumor Associated Macrophages And Microglia Drive Tumor Progression And Are Transcriptionally Shaped By Histone Mutations In Pediatric Diffuse Midline Glioma

Project description:Pediatric high-grade gliomas, including diffuse midline gliomas (DMG), harbor mutually exclusive tumor location specific histone mutations. Using immunocompetent genetically engineered mouse models, we demonstrate the predominant non-neoplastic cell population are infiltrating myeloid cells, including peripheral monocytes and brain resident microglia. Single cell RNA sequencing, flow cytometry, and immunohistochemistry demonstrate the presence of unique myeloid cell populations distinctly shaped by the specific histone mutation. Disease associated myeloid cell phenotypes are identified, resembling those found in other neurodegenerative diseases, and demonstrate immune permissive characteristics. H3.3K27M DMGs, the most aggressive DMG subtype, demonstrate enrichment of disease associated myeloid cells as well as proliferating myeloid and tumor cells.

2024-10-11 | GSE245716 | GEO

Histone H3.3K27M mutation activates multiple cancer/testis antigens

Project description:Lysine27Methionine mutations (K27M) in the histone H3 (H3.3 and H3.1) are highly prevalent in pediatric high-grade gliomas (HGG). This study found H3.3K27M caused the upregulation of multiple cancer/testis (CT) antigens, include IL13RA2 and VCX family proteins. Overexpression of VCX3A/B stimulates the expression of genes involved in immune response.

2018-08-01 | GSE102886 | GEO

Boswellic acid formulations are not suitable for additive treatment of pediatric high-grade glioma

Project description:Introduction: Pediatric high-grade gliomas (pedHGG) comprise a very poor prognosis. Thus, parents of affected children are increasingly resorting to complementary and alternative medicine (CAM). Among others, one of the most frequently used CAM are boswellic acids (BA). Methods: The therapeutic effectiveness of the three main BA, alpha-boswellic acid (α-BA), beta-boswellic acid (β-BA) and 3-acetyl-11-keto-beta-boswellic acid (AKBA) was analyzed in a histone 3 (H3)-wildtype and a H3.3K27M-mutant pedHGG cell line, either alone or in combination with radiotherapy and/or temozolomide chemotherapy. Cell viability, stemness properties and apoptosis as well as mRNA sequencing and in ovo tumor growth was investigated upon BA treatment. Results: Whereas α-BA and β-BA exert only mild anti-tumor effects in H3WT and H3.3K27M-mutated pedHGG cells, AKBA treatment reduced cell viability and stemness potential especially in H3.3K27M-mutant pedHGG cells. In addition, slight anti-inflammatory effects were observed after AKBA treatment of H3.3K27M-mutant pedHGG cells. However, no effects on apoptosis and in ovo tumor growth were found. Of note, α-BA and β-BA treatment even resulted in tumor promoting effects in both pedHGG cells.

2023-08-15 | GSE214897 | GEO

H3.3K27M cooperates with p53 loss and Pdgfra gain in mouse embryonic neural progenitor cells to induce invasive high-grade gliomas [Mouse RNA-Seq]

Project description:Gain-of-function mutations in histone 3 (H3) variants are found in a large proportion ofpediatric high-grade gliomas (pHGG) and are often associated with p53 loss and PDGFRA amplification. However, a lack of faithful models has hampered investigation of disease mechanisms and preclinical development. Here, we describe a somatic mouse model of H3.3K27M-driven HGG, which faithfully recapitulates human H3.3K27M pHGG. H3.3K27M and p53 loss are sufficient for neoplastic transformation but only within a specific window of brain development. In this model, H3.3K27M primes the PDGFRA pathway during transformation, and accordingly gain of wild-type PDGFRA decreases latency and increases invasion. Finally, we reveal a previously underappreciated dynamic regulation of H3K27 trimethylation at specific loci. Overall, this experimental model provides key insights into oncohistone-driven pHGG pathogenesis and will enable investigations of future therapies.

2017-10-27 | GSE95168 | GEO

H3.3K27M cooperates with p53 loss and Pdgfra gain in mouse embryonic neural progenitor cells to induce invasive high-grade gliomas [Mouse ChIP-Seq]

2017-10-27 | GSE95167 | GEO

H3.3K27M cooperates with p53 loss and Pdgfra gain in mouse embryonic neural progenitor cells to induce invasive high-grade gliomas [Mouse WES]

2017-10-27 | GSE100826 | GEO

A Novel Mouse Model of Diffuse Midline Glioma Initiated in Neonatal Oligodendrocyte Progenitor Cells Highlights Cell- of-origin Dependent Effects of H3K27M I

Project description:Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A or PDGF-B overexpression, along with p53 deletion, resulted in gliomas in both models. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, both in PDGF-A and PDGF-B-driven models, suggesting that the requirement for H3.3K27M is increased when tumorigenesis is initiated in Nestin+ cells. Therefore, we need to find how the tumorigenic effects of H3.3K27M are more oncogenic in Nestin+ cells than Olig2+ cells.

2021-10-05 | GSE184934 | GEO

MHC-II immunopeptidome for CNS injury model

Project description:In homeostasis, because of the blood-brain barrier, immune cells rarely infiltrate the central nervous system (CNS). However, after spinal cord injury (SCI), many cells, including both myeloid and T cells, infiltrate the spinal cord. However, the role immune cells play in SCI remains controversial. We are curious whether after SCI there are self-peptides that are released and sensed by T cells that then modulate response to CNS injury.

2023-01-24 | MSV000091130 | MassIVE

H3.3K27M cooperates with p53 loss and Pdgfra gain in mouse embryonic neural progenitor cells to induce invasive high-grade gliomas [Human RNA-Seq]

Project description:Gain-of-function mutations in histone 3 (H3) variants are found in a large proportion of pediatric high-grade gliomas (pHGG) and are often associated with p53 loss and PDGFRA amplification. However, a lack of faithful models has hampered investigation of disease mechanisms and preclinical development. Here, we describe a somatic mouse model of H3.3K27M-driven HGG, which faithfully recapitulates human H3.3K27M pHGG. H3.3K27M and p53 loss are sufficient for neoplastic transformation but only within a specific window of brain development. In this model, H3.3K27M primes the PDGFRA pathway during transformation, and accordingly gain of wild-type PDGFRA decreases latency and increases invasion. Finally, we reveal a previously underappreciated dynamic regulation of H3K27 trimethylation at specific loci. Overall, this experimental model provides key insights into oncohistone-driven pHGG pathogenesis and will enable investigations of future therapies.

2017-10-27 | GSE95277 | GEO

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