Neuro-oncology最新文献

Background: Relapsed medulloblastoma remains a significant therapeutic challenge as it is near universally fatal. The tumor microenvironment of medulloblastoma plays a critical role in tumor progression, influencing tumor growth, immune evasion, and therapeutic resistance. We hypothesised that defining tumor-immune interactions in diagnostic and relapsed medulloblastoma may uncover mechanisms of immune evasion and identify novel therapeutic targets.

Methods: We analysed paired primary and recurrent RNA-sequencing data from 140 medulloblastoma patients to profile immune cell composition and validate spatial relationships within the tumor microenvironment. To identify key tumor-immune interactions, we developed a novel algorithm to detect receptor-ligand pairs using single cell RNA-sequencing data. These interactions were validated across RNA and proteomic datasets. Their functional significance was empirically demonstrated in newly developed immunocompetent models of recurrent medulloblastoma that closely recapitulate the human disease.

Results: We observed a shift in toward a heightened immunosuppressive tumor microenvironment at relapse. Using our algorithm, we identified biologically significant receptor-ligand interactions, most notably MIF-CD74, constitutively expressed at RNA and protein levels across medulloblastoma subgroups, at diagnosis and relapse. Disrupting MIF-CD74 interactions led to significant alterations in the tumor microenvironment, highlighting its functional significance.

Conclusions: Our multifaceted approach identified key tumor-immune interactions in medulloblastoma. Among these, MIF-CD74 was validated as a targetable interaction, demonstrating the utility of our integrative approach for identifying novel therapeutic targets across multiple tumor types.

Plexiform neurofibromas (PNs) are a hallmark of neurofibromatosis type 1 (NF1), affecting ∼50% of individuals with the condition. Originating from Schwann cells and other peripheral nerve sheath components, these tumors can cause significant morbidity, including functional impairment, diminished health-related quality of life, chronic pain, and malignant transformation. Managing NF1-PNs is challenging because of disease variability, differing growth rates, and age-related differences in clinical presentation and treatment tolerability. This review examines current therapeutic strategies, including surgery, medical therapies, and emerging treatments, emphasizing individualized care. Highlighted here is the need for age-specific treatment planning, particularly as disease progression, comorbidities, and side-effect profiles differ between pediatric and adult patients. Optimizing outcomes requires personalized surveillance and coordinated multidisciplinary management across all age groups. While MEK inhibitors (MEKi) provide therapeutic benefit, their long-term efficacy and safety, particularly in pediatric patients who may receive these agents for extended periods, warrant further investigation. Additionally, adult patients face unique comorbidities that may complicate therapy. Superficial PNs and potential MEK inhibitor resistance remain underexplored. Growing interest in combination therapies and adjuvant strategies may improve outcomes. Ongoing research is crucial to personalize treatment regimens, to identify effective combinations, and to refine surveillance protocols, ultimately enhancing long-term quality of life for individuals living with NF1-PN.

Background: Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor affecting over 300 children annually in the United States. Chimeric antigen receptor (CAR) T cells are a targeted immune effector cell therapy with substantial clinical benefit against hematologic cancers. Against CNS tumors, CAR T cells targeting B7-H3, a protein highly expressed on DIPG, have rapidly advanced from preclinical studies to clinical trials. BrainChild-03 (NCT04185038), a phase 1 trial of repeatedly delivered intracerebroventricular (ICV) B7-H3-targeting CAR T cells (B7-H3 CAR T cells), demonstrated tolerability and potential efficacy for children and young adults with DIPG. However, clinical benefits were not uniformly seen, and multi-agent treatment strategies may be required against such an aggressive disease. Here, we combined B7-H3 CAR T cells with ONC206, an imipridone molecule also under clinical investigation.

Methods: We tested B7-H3 CAR T cells combined with ONC206 across multiple DIPG cell cultures and orthotopic xenograft mouse models.

Results: B7-H3 CAR T cell monotherapy induced robust cytotoxicity while ONC206 treatment resulted in significant mitochondrial dysfunction against DIPG cells. The combination of low effector-to-target ratios of B7-H3 CAR T cells and IC50 concentrations of ONC206 led to significantly enhanced cytotoxicity in vitro (p < 0.003) and increased IL-2, IL-29, VEGF-A, and Granzyme B levels. In vivo combinatorial studies of ONC206 and a single ICV dose of B7-H3 CAR T cells extended survival in DIPG xenograft mouse models.

Conclusions: B7-H3 CAR T cells combined with ONC206 is a feasible and efficacious multi-agent approach against multiple DIPG models.

Background: Mechanisms driving aggressive meningiomas remain poorly understood. Given the pivotal role of the immune microenvironment in tumor progression, we developed a comprehensive atlas of the meningioma microenvironment, with a view towards identifying modifiable opportunities.

Methods: The immune microenvironment of 2,727 meningiomas was profiled using orthogonal methodologies, including 24 with mass cytometry, 24 single-cell RNAseq, 1,437 bulk RNAseq, 1,125 DNA methylation, 117 multiplex immunofluorescence, as well as that of 5 paired peripheral blood samples and 10 human meninges. Patient-derived organotypic tumor spheroids (PDOTS) were established to assess the effect of STING stimulation combined with anti-PD-1 treatment.

Results: We revealed a rich immune infiltration in meningioma, among the highest across 34 human cancer types (n = 12,188). Macrophages predominated in meningioma microenvironment, in contrast to the lymphoid dominance of peripheral blood, with meninges exhibiting an intermediate immune profile between meningiomas and peripheral blood. Cellular states and phenotypes of both immune and tumor cells shifted during tumor progression, with aggressive meningiomas possessing earlier-stage, immunosuppressive immune cells and proliferative tumor cells. Using ex vivo meningioma PDOTS, we demonstrated inducible responses to STING activation, marked by elevated cytokine release, which were synergistic when combined with PD-1 blockade.

Conclusions: These findings offer an extensive resource on the cellular heterogeneity of the meningioma microenvironment and provide a framework for rational therapeutic modeling and strategy development.

Diffuse midline glioma, H3 K27-altered, formerly known as diffuse intrinsic pontine glioma, (DIPG/DMG) is the most aggressive form of pediatric brain malignancy, with <10% 2-year overall survival after standard of care. The limited success of traditional immune checkpoint inhibitors in pediatric high-grade gliomas, including DMG, has highlighted the urgent need to re-examine the tumor's intrinsic and microenvironmental barriers to immunotherapy. Advances in molecular and spatial profiling have revealed the profound intratumoral heterogeneity, lineage plasticity, and complex immunosuppressive tumor microenvironment characteristic of DMG, which are shaped by diverse myeloid populations, neuronal integration, and spatially distinct tumor niches. These insights are informing the development of non-traditional immunotherapeutic approaches, including alternative checkpoint blockade, chimeric antigen receptor T cells, and viro-immunotherapy strategies, which aim to overcome DMG's unique immune escape mechanisms. We also outline key translational challenges and future directions necessary to accelerate progress, including the refinement of preclinical models, optimization of CNS-specific immunotherapy delivery, and the integration of patient-derived data into streamlined, collaborative clinical trial platforms.

Background: Metastasis remains a critical determinant of survival in neuroblastoma (NB), yet the role of transcriptional dysregulation, particularly super-enhancer (SE)-mediated transcriptional control in this process has not been elucidated. The aim of this study is to identify the SE-driven transcription factors involved in the metastasis of NB and potential targeted drugs.

Methods: The metastatic SE-driven Transcription Factor 4 (TCF4) was screened and identified by integrating bioinformatic analyses of H3K27ac ChIP-seq and scRNA-seq. The effect of TCF4 on NB cell metastasis was evaluated through in vivo and in vitro functional experiments. The molecular mechanism of TCF4 was investigated by the study of targeted CUT&Tag and transcriptome sequencing.

Results: TCF4 is associated with poor prognosis in patients and significantly promotes the metastasis ability of NB cells both in vivo and in vitro. Mechanistically, TCF4 transcriptionally activates SPTLC1, a pivotal enzyme in sphingolipid biosynthesis, to promote ganglioside GM3 synthesis. GM3 orchestrates membrane architecture remodeling, thereby modulating ITGB1 membrane localization and activation, which subsequently potentiates FAK signaling. Notably, we demonstrate that the HDAC6 inhibitor ACY-1215 suppressed NB malignancy by destabilizing TCF4 protein.

Conclusions: Our findings indicate that SE-driven TCF4 can orchestrate metastatic transcriptional networks to maintain NB malignancy and propose ACY-1215 as a translational therapeutic candidate for clinical intervention.

Background: Immunotherapies have improved outcomes in many cancers but remain largely ineffective in glioblastoma (GBM). We investigated whether immunotherapy could be rationally tailored to GBM by functionally subtyping the tumor immune microenvironment (TIME) and associated vascular landscapes.

Methods: Single-cell and single-nucleus RNA sequencing, multiplex immunohistochemistry and flow cytometry were used to define TIME subtypes in human and murine GBMs. Therapeutic responses to anti-angiogenic and immunomodulatory therapies, including CD40 agonism, anti-PDL1, and PI3Kγ/δ inhibition, were assessed in orthotopic syngeneic GBM mouse models.

Results: Three distinct functional TIME subtypes with unique vascular-immune landscapes were identified in human and murine GBM. TIME-low tumors were immune-low/deserted with a leaky vasculature. TIME-med GBM exhibited intermediate immune-infiltration, prominent angiogenesis and active immune responses. TIME-high tumors showed dense infiltration of immunosuppressive myeloid cells and dysfunctional T cells. Representative mouse models demonstrated subtype-specific sensitivities to anti-angiogenic immunomodulating therapies. TIME-low GBMs exhibited transient T-cell activation but relapsed due to myeloid-driven immunosuppression and mesenchymal transition. TIME-med tumors displayed the most favorable responses across anti-angiogenic immunomodulating therapies. TIME-high GBMs were largely resistant, although therapeutic efficacy improved with myeloid-targeted PI3Kγ inhibition. In contrast, CD40 agonist therapy worsened survival by enhancing angiogenesis, amplifying immunosuppression, impairing T cell function, reducing NK-cell recruitment, and promoting tumor propagation.

Conclusions: GBM comprise three functional TIME subtypes with divergent vascular-immune landscapes that require subtype-specific therapeutic strategies. TIME-med tumors are most amenable to immunotherapies. TIME-low tumors derive transient effects with anti-angiogenic immunomodulating therapies, and TIME-high are resistant or even experience worse outcome without targeted reversal of myeloid immunosuppression.

Background: Genomic stability is essential for cell survival, particularly under stress conditions like hypoxia, which disrupt DNA repair. Glioblastoma (GBM) is markedly resistant to DNA-damaging therapies, primarily due to glioma stem cells (GSCs) and the hypoxic tumor microenvironment. Long non-coding RNAs (lncRNAs) play a significant role in maintaining genome integrity, but their involvement in the DNA damage response (DDR) under hypoxic conditions in GSCs remains unclear. We previously identified LUCAT1 as the most highly induced lncRNA in GSCs under hypoxia and a key regulator HIF1α activity. We now investigate its role in DDR regulation.

Methods: LUCAT1-interacting proteins in GSCs under hypoxia were identified using identification of direct RNA interacting proteins (iDRIP) and mass spectrometry. Interactions were confirmed by RNA pulldown and RNA immunoprecipitation. Mechanistic studies involved immunoprecipitation, proximity ligation assays, comet assays, immunostaining, and LUCAT1 knockdown using shRNA. Gene expression changes were evaluated via RNAseq in GSCs and TCGA datasets. Functional assays were conducted in GSCs and orthotopic xenografts with LUCAT1 depletion alone or in combination with PARP or DNA-PK inhibition or radiation.

Results: LUCAT1 directly interacts with the DNA-PK holoenzyme, modulating its assembly and function in the non-homologous end joining (NHEJ) pathway. It also regulates BRCA1 and RAD51, key proteins in homologous recombination (HR). Depletion of LUCAT1 increased DNA damage, sensitized GSCs to DDR inhibitors, and improved survival in mice treated with radiotherapy.

Conclusions: LUCAT1 is a critical DDR regulator in GSCs under hypoxia and a promising target to enhance the efficacy of DDR inhibitors and radiotherapy in GBM.

Ependymoma represents a biologically and clinically heterogeneous group of glial tumours that arise throughout the whole neuroaxis and in all age groups. Whereas intracranial ependymoma is usually found in children, adults suffer mostly from spinal cord ependymoma. In comparison to other neuro-oncological tumour entities, ependymoma has been largely understudied for decades. However, the recent years resulted in unprecedented progress with regard to the understanding of the biological underpinnings and clinical features of ependymoma. Here, we review the history of ependymoma research with a focus on the development of classification models throughout the years and a discussion of the most important clinical trials that have led to the current therapeutic standard, comprising maximal safe resection and, in most cases, radiotherapy. Critically, the evidence for effective drugs and chemotherapies in ependymoma is still sparse. However, these important questions may be soon addressed with the finalisation of the currently unpublished last generation of multi-institutional trials in Europe (SIOP EP II) and Northern America (ACNS0831). Lastly, we discuss the current challenges in the field of ependymoma research and the necessary next steps towards the goal of findings cures for all types of ependymal tumours.

Background: Intracranial solitary fibrous tumors (SFTs) are rare, aggressive neoplasms with high local recurrence. This study evaluates the efficacy and prognostic factors of single-fraction stereotactic radiosurgery (SRS).

Methods: This multicenter retrospective study included 107 patients (253 SFTs) treated with single-fraction SRS at 18 centers (1989-2024). We analyzed local control (LC), intracranial tumor control (ITC), overall tumor control (OTC), progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS). Cox regression identified prognostic factors.

Results: Median follow-up was 33 months. LC was 68.4% (5-yr: 56.8% and 10-yr: 38.8%). ITC 54.2% (5-yr: 48.5%) and OTC 50.5% (5-yr: 44.0%). PFS was 56.3% and 30.2% at 5 and 10 years, respectively. DSS remained high at 89.7% (5-yr) and 79.7% (10-yr), while OS was 79.3% (5-yr) and 55.2% (10-yr). Independent predictors of LC included recurrent vs. metastatic SFTs (HR: 1.96, p = 0.028), margin dose ≤16 Gy (HR: 2.35, p = 0.006), larger tumor volume (HR: 1.05, p < 0.001), and longer diagnosis-to-SRS duration (HR : 1.02, p < 0.001). Older age (HR: 1.03, p = 0.014) and longer resection-to-SRS duration (HR: 1.02, p = 0.018) predicted worse ITC. Age significantly affected OS (HR: 1.06, p < 0.001) and PFS (HR: 1.03, p = 0.037). Longer diagnosis-to-SRS (HR: 1.03, p = 0.002) and resection-to-SRS durations (HR : 1.02, p = 0.030) predicted worse PFS. KPS score >70 predicted better outcomes across ITC, OTC, DSS and OS. Radiation-related adverse effects occured in 2.8%.

Conclusion: SRS offers reasonable tumor control and favorable long-term survival in the adjuvant and salvage setting for patients with residual, recurrent, or metastatic intracranial SFTs. Key prognostic factors included tumor volume, recurrence status, and timing of SRS.