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<p>Medulloblastoma (MB) is the most common malignant brain tumor in children, comprising four distinct subgroups: <i>wingless</i> (WNT), <i>sonic hedgehog</i> (SHH), Group 3, and Group 4. <i>MYC</i> amplification and metastatic dissemination are challenges in clinical management, and tumor-associated macrophages (TAMs) play an essential role in these intricate molecular processes. However, the influence of immune cells in MB metastasis and <i>MYC</i>-amp is unclear. Secretion of extracellular vesicles (EVs) has emerged as a pivotal mediator facilitating communication within the tumor microenvironment, orchestrating coordinated responses among immune cells during tumor initiation, progression, and tumor dissemination. Here, we sought to elucidate the role of exosome-derived MBs in promoting specific patterns of TAM polarization across different molecular subgroups of MB cell lines. CIBERSORTx analysis using a single-cell RNA dataset revealed an increase in M0 macrophages and a decreased proportion of M2 macrophages in MB patients with tumor dissemination in the central nervous system (CNS). Cell-derived exosomes were found to secrete high levels of IL-4, IL-10, and TGF-β, indicative of a protumor M2-profile pattern. Moreover, EVs from SHH <i>TP53</i>-mutated, Group 3/4, and <i>MYC</i>-amplified MBs induced dissimilar patterns of TNF-α and/or IL-1β overexpression. This study demonstrates that exosomes from pediatric MBs promote a predominant M2-macrophage phenotype and Group 3, Group 4, SHH <i>TP53</i>-mutated, and <i>MYC</i>-amplified MBs induced a mixed M1/M2 response pattern. These findings shed light on the pivotal role of exosomes in modulating the immune response, potentially contributing to immune escape in this malignant neoplasm.</p>

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Immunomodulatory role of exosome-derived content in pediatric medulloblastoma: a molecular subgroup perspective

  • 期刊论文

  • 发表日期：

    2025年2月17日

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  • Jessica Oliveira de Santis,
  • Graziella Ribeiro de Sousa,
  • Rosane Gomes de Paula Queiroz,
  • Marina Ferreira Cândido,
  • Fausto Almeida,
  • Caroline Patini de Rezende,
  • Patricia Cassia de Ruy,
  • Gabriel Santos Arini,
  • Beth Coyle,
  • Philippa Wade,
  • María Sol Brassesco,
  • Carlos Alberto Scrideli,
  • Luiz Gonzaga Tone,
  • Elvis Terci Valera

摘要

Medulloblastoma (MB) is the most common malignant brain tumor in children, comprising four distinct subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. MYC amplification and metastatic dissemination are challenges in clinical management, and tumor-associated macrophages (TAMs) play an essential role in these intricate molecular processes. However, the influence of immune cells in MB metastasis and MYC-amp is unclear. Secretion of extracellular vesicles (EVs) has emerged as a pivotal mediator facilitating communication within the tumor microenvironment, orchestrating coordinated responses among immune cells during tumor initiation, progression, and tumor dissemination. Here, we sought to elucidate the role of exosome-derived MBs in promoting specific patterns of TAM polarization across different molecular subgroups of MB cell lines. CIBERSORTx analysis using a single-cell RNA dataset revealed an increase in M0 macrophages and a decreased proportion of M2 macrophages in MB patients with tumor dissemination in the central nervous system (CNS). Cell-derived exosomes were found to secrete high levels of IL-4, IL-10, and TGF-β, indicative of a protumor M2-profile pattern. Moreover, EVs from SHH TP53-mutated, Group 3/4, and MYC-amplified MBs induced dissimilar patterns of TNF-α and/or IL-1β overexpression. This study demonstrates that exosomes from pediatric MBs promote a predominant M2-macrophage phenotype and Group 3, Group 4, SHH TP53-mutated, and MYC-amplified MBs induced a mixed M1/M2 response pattern. These findings shed light on the pivotal role of exosomes in modulating the immune response, potentially contributing to immune escape in this malignant neoplasm.