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Updated: May 23, 2025
Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
Tumor-associated macrophage-derived exosomes modulate the immunotherapeutic sensitivity of SHH-medulloblastoma by
Yantao Liu1,2,3, Yu Peng1,2,3, Chen Song4,5
1Beijing Key Laboratory of Research and Transformation of Biomarkers for Neurodegenerative Diseases, Peking University Third Hospital, Peking University Health Science Center, Beijing, China.
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.
Conclusions:
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.
Insights
Tumor-associated macrophages in Sonic Hedgehog medulloblastoma release exosomes that decrease RNA m6A modification via FOXD1, promoting tumor growth. Inhibiting FOXD1 enhances anti-PD-1 therapy effectiveness.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Medulloblastoma (MB) is the most common pediatric brain tumor.
- Tumor-associated macrophages (TAMs) and RNA N6-methyladenosine (m6A) modification are linked to poor prognosis in Sonic Hedgehog MB (SHH-MB).
- The interplay between TAM infiltration and m6A status in SHH-MB progression is not well understood.
Purpose of the Study:
- To investigate the relationship between TAM infiltration, m6A modification, and tumor progression in SHH-MB.
- To identify the mechanisms by which TAMs influence m6A levels in SHH-MB.
- To evaluate FOXD1 as a therapeutic target in SHH-MB.
Main Methods:
- Assessed m6A-related protein expression in 40 SHH-MB cases.
- Used methylated RNA immunoprecipitation sequencing to identify genes affected by TAM-derived exosomes.
- Investigated FOXD1 m6A modification mechanisms and combinatorial therapy in a mouse model.
Main Results:
- TAM infiltration decreased METTL14 expression and m6A levels, mediated by TAM-derived exosomes.
- FOXD1 was identified as a key downstream target of TAM exosomes, correlating with poor prognosis.
- FOXD1 knockdown promoted chemokine release, enhancing CD8+ T cell recruitment and anti-tumor effects of PD-1 inhibitors in mice.
Conclusions:
- TAM-derived exosomes modulate m6A levels in SHH-MB, promoting tumor progression through FOXD1.
- FOXD1 is a novel therapeutic target that sensitizes SHH-MB to immune checkpoint blockade.
