Tumor-associated macrophage-derived exosomes modulate the immunotherapeutic sensitivity of SHH-medulloblastoma by targeting m6A-modified FOXD1
Menée à l'aide de lignées cellulaires, d'un modèle murin transgénique et d'échantillons de médullobastomes de type SHH, cette étude met en évidence un mécanisme par lequel les exosomes issus des macrophages TAM, en augmentant l'expression de FOXD1 via la réduction du niveau intratumoral de n6 méthyladénine (m6A), favorisent l'immunosuppression ainsi que la progression tumorale
Background : Medulloblastoma (MB) is the most common pediatric malignant brain tumor. Infiltration of tumor-associated macrophages (TAMs) and m6A modification of RNA are correlated with poor prognosis and tumor progression in the Sonic Hedgehog (SHH) subtype (SHH-MB). However, the relationship between TAMs infiltration in SHH-MB and m6A modification status during tumor progression remains unclear.
Methods : Expression of m6A modification-related proteins was assessed in 40 cases of SHH-MB. Genes affected by TAM-derived exosomes were identified with methylated RNA immunoprecipitation sequencing. Mechanisms of m6A modification of FOXD1 were evaluated and combinatorial treatment with AAV2/9-shFOXD1 and PD-1 inhibitors was investigated in the NeuroD2:SmoA1 mouse model.
Results : TAMs infiltration led to decreased METTL14 expression, which was mediated by TAM-derived exosomes containing METTL14-specific microRNAs. In turn, this led to lower levels of m6A modifications. Through a screen, FOXD1 was identified as a critical downstream target of TAM-derived exosomes, and its expression level was correlated with poor prognosis in SHH-MBs. Importantly, knockdown of FOXD1 in SHH-MB cells significantly promoted the release of chemokines CXCL10/11, resulting in CD8+ T cell recruitment. Furthermore, treatment with AAV2/9-shFOXD1 significantly enhanced the antitumor effect of the PD-1 inhibitor in transgenic SHH-MB mice.
Conclusion : Our study revealed for the first time that TAM-derived exosomes modulate m6A levels in SHH-MB, which promotes tumor progression via FOXD1. We identified FOXD1 as a novel therapeutic target whose inhibition sensitizes SHH-MB to immune checkpoint blockade.
Neuro-Oncology , article en libre accès, 2025