The Tumor Microenvironment of Medulloblastoma: An Intricate Multicellular Network with Therapeutic Potential

Bree, Niek van; Wilhelm, Margareta

doi:10.3390/cancers14205009

Cited by 11 publications

(9 citation statements)

References 162 publications

(214 reference statements)

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“…Altogether, these lines of evidence indicate that MB cells can be susceptible to immune-mediated attack (Eisemann and Wechsler-Reya, 2022). However, immune evasion mechanisms have been reported for MB immunosuppressive environment (Eisemann and Wechsler-Reya, 2022) (Bockmayr et al, 2018) (van Bree andWilhelm, 2022), including the loss of MHC class I on the tumor cell (Vermeulen et al, 2018), and the secretion of TGF-β (Gate et al, 2014;Bockmayr et al, 2018;Powell et al, 2019), especially in metastatic GR3 MB (Ferrucci et al, 2018) that acts as a chemoattractant for T-regs (Gate et al, 2014;Bockmayr et al, 2018;Vermeulen et al, 2018 #83;Grabovska et al, 2020) (Gururangan et al, 2017) and induces downregulation of NKG2D ligands on tumor cells (Haberthur et al, 2016), thus reducing the recruitment of activated NK cells (Vermeulen et al, 2018).…”

Section: Discussionmentioning

confidence: 96%

Epigenetics and immune cells in medulloblastoma

et al. 2023

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Medulloblastoma (MB) is a highly malignant childhood tumor of the cerebellum. Transcriptional and epigenetic signatures have classified MB into four molecular subgroups, further stratified into biologically different subtypes with distinct somatic copy-number aberrations, driver genes, epigenetic alterations, activated pathways, and clinical outcomes. The brain tumor microenvironment (BTME) is of importance to regulate a complex network of cells, including immune cells, involved in cancer progression in brain malignancies. MB was considered with a “cold” immunophenotype due to the low influx of immune cells across the blood brain barrier (BBB). Recently, this assumption has been reconsidered because of the identification of infiltrating immune cells showing immunosuppressive phenotypes in the BTME of MB tumors. Here, we are providing a comprehensive overview of the current status of epigenetics alterations occurring during cancer progression with a description of the genomic landscape of MB by focusing on immune cells within the BTME. We further describe how new immunotherapeutic approaches could influence concurring epigenetic mechanisms of the immunosuppressive cells in BTME. In conclusion, the modulation of these molecular genetic complexes in BTME during cancer progression might enhance the therapeutic benefit, thus firing new weapons to fight MB.

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Section: Discussionmentioning

confidence: 96%

Epigenetics and immune cells in medulloblastoma

et al. 2023

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“…Despite the promising results obtained in pre-clinical models, further investigations need to be conducted to evaluate if these strategies can be applied in a clinical context, allowing the development of new therapeutic approaches. CSCs are not isolated inside tumor bulk, since this has been extensively reported since they are surrounded by a complex TME [ 126 , 127 ].…”

Section: Future Perspectivesmentioning

confidence: 99%

Nanoparticles for Drug and Gene Delivery in Pediatric Brain Tumors’ Cancer Stem Cells: Current Knowledge and Future Perspectives

et al. 2023

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Primary malignant brain tumors are the most common solid neoplasm in childhood. Despite recent advances, many children affected by aggressive or metastatic brain tumors still present poor prognosis, therefore the development of more effective therapies is urgent. Cancer stem cells (CSCs) have been discovered and isolated in both pediatric and adult patients with brain tumors (e.g., medulloblastoma, gliomas and ependymoma). CSCs are a small clonal population of cancer cells responsible for brain tumor initiation, maintenance and progression, displaying resistance to conventional anticancer therapies. CSCs are characterized by a specific repertoire of surface markers and intracellular specific pathways. These unique features of CSCs biology offer the opportunity to build therapeutic approaches to specifically target these cells in the complex tumor bulk. Treatment of pediatric brain tumors with classical chemotherapeutic regimen poses challenges both for tumor location and for the presence of the blood–brain barrier (BBB). Lastly, the application of chemotherapy to a developing brain is followed by long-term sequelae, especially on cognitive abilities. Novel avenues are emerging in the therapeutic panorama taking advantage of nanomedicine. In this review we will summarize nanoparticle-based approaches and the efficacy that NPs have intrinsically demonstrated and how they are also decorated by biomolecules. Furthermore, we propose novel cargoes together with recent advances in nanoparticle design/synthesis with the final aim to specifically target the insidious CSCs population in the tumor bulk.

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“…The intricate interplay between the infiltrative nature of medulloblastoma and the intricacies of neural architecture demands precise and efficacious therapeutic strategies [6]. Within this context, stereotactic radiosurgery (SRS) has emerged as a focal point in the management of recurrent medulloblastoma [7].…”

Section: Introductionmentioning

confidence: 99%

The Role of CyberKnife Stereotactic Radiosurgery in Recurrent Cranial Medulloblastomas across Pediatric and Adult Populations

Yoo,

Marianayagam,

Park

et al. 2024

Preprint

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Background and Objectives: Medulloblastoma is the most common malignant brain tumor in children. In recent decades, the therapeutic landscape has undergone significant changes, with stereotactic radiosurgery (SRS) emerging as a promising treatment for recurrent cases. Our study provides a comprehensive analysis of the long-term efficacy and safety of SRS in recurrent medulloblastomas across both pediatric and adult patients at a single institution. Methods: We retrospectively reviewed the clinical and radiological records of patients who underwent CyberKnife SRS for recurrent cranial medulloblastomas at our institution between 1998 and 2023. Follow-up data were available for 15 medulloblastomas in 10 patients. The cohort comprised 8 pediatric patients (ages 3-18) and 2 adult patients (ages 19-75). Median age at the time of SRS was 13 years, median tumor volume accounted for 1.9 cc, median biologically equivalent dose (BED) was 126 Gy, and single-fraction equivalent dose (SFED) was 18 Gy. The SRS was administered at 75% of the median isodose line. Results: Following a median follow-up of 39 months (range: 6-78), 53.3% of the medulloblastomas progressed, 13.3% regressed, and 33.3% remained stable. The 3-year local tumor control (LTC) rate for all medulloblastomas was 65%, with lower rates observed in the adult cohort (50%) and higher rates in pediatric patients (67%). The 3-year overall survival (OS) rate was 70%, with significantly higher rates in pediatric patients (75%) compared to adult patients (50%). The 3-year progression-free survival (PFS) rate was 58.3%, with higher rates in pediatric patients (60%) compared to adult patients (50%). Two pediatric patients developed radiation-induced edema, while two adult patients experienced radiation necrosis at the latest follow-up, with both adult patients passing away. Conclusion: Our study provides a complex perspective on the efficacy and safety of CyberKnife SRS in treating recurrent cranial medulloblastomas across pediatric and adult populations. The rarity of adverse radiation events (ARE) underscores the safety profile of SRS, reinforcing its role in enhancing treatment outcomes. The intricacies of symptomatic outcomes, intertwined with factors such as age, tumor location, and prior surgeries, emphasize the need for personalized treatment approaches. Our findings underscore the imperative for ongoing research and the development of more refined treatment strategies for recurrent medulloblastomas. Given the observed disparities in treatment outcomes, a more meticulous tailoring of treatment approaches becomes crucial.

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The Tumor Microenvironment of Medulloblastoma: An Intricate Multicellular Network with Therapeutic Potential

Cited by 11 publications

References 162 publications

Epigenetics and immune cells in medulloblastoma

Epigenetics and immune cells in medulloblastoma

Nanoparticles for Drug and Gene Delivery in Pediatric Brain Tumors’ Cancer Stem Cells: Current Knowledge and Future Perspectives

The Role of CyberKnife Stereotactic Radiosurgery in Recurrent Cranial Medulloblastomas across Pediatric and Adult Populations

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