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Published on: December 3, 2019
Single-cell transcriptomics reveals MAFB-driven macrophage reprogramming and immune divergence in recurrent
Yijing He1,2, Jiaming Yu3, Meng Huang4
1Center for Stem Cell Biology and Tissue Engineering, Key Laboratory of Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China.
Background:
Glioblastoma (GBM) is the most aggressive and most common type of primary brain tumor, with poor prognosis despite standard therapies. The mechanisms driving recurrence remain poorly understood. Tumor-associated macrophages (TAM) dominate the GBM microenvironment and promote tumor growth, angiogenesis, and immune suppression, yet their activation states and transcriptional programs are not well defined.
Results:
By integrating large-scale single-cell transcriptomic datasets, we delineate profound immune microenvironmental divergence in recurrent GBM, characterized by the emergence of a distinct CXCL3⁺ tumor-associated macrophage (TAM) population. These CXCL3⁺ TAMs exhibit a robust pro-inflammatory cytokine program, intensified interactions with malignant and immunosuppressive immune cells, and a strong association with poor patient survival. Regulatory network analysis identifies MAFB as the central transcriptional regulator of this TAM state. MAFB is selectively enriched in macrophages, markedly upregulated in recurrent tumors, and strongly correlated with pro-inflammatory gene signatures. Immunohistochemistry and multiplex immunofluorescence further demonstrate an expanded population of MAFB⁺ mesenchymal-like TAMs in recurrent GBM. Depletion of MAFB in patient-derived GBM cells suppresses intracranial tumor growth and prolongs survival in vivo.
Conclusions:
Our study highlights profound immune remodeling in primary and recurrent GBM. We further define a MAFB-driven CXCL3⁺ macrophage program that shapes the immune landscape of recurrent GBM and underscore this axis as a promising target for microenvironmental reprogramming.
Insights
Recurrent glioblastoma (GBM) features a distinct CXCL3⁺ tumor-associated macrophage (TAM) population regulated by MAFB. Targeting this MAFB-driven macrophage program may offer new therapeutic strategies for aggressive brain tumors.
Area of Science:
- Neuro-oncology
- Immunology
- Genomics
Background:
- Glioblastoma (GBM) is an aggressive primary brain tumor with poor outcomes.
- Mechanisms of GBM recurrence are not well understood.
- Tumor-associated macrophages (TAMs) influence GBM growth and immune suppression.
Purpose of the Study:
- To investigate immune microenvironmental changes in recurrent GBM.
- To define the role of TAMs in GBM recurrence.
- To identify therapeutic targets for GBM.
Main Methods:
- Single-cell transcriptomic data integration.
- Regulatory network analysis.
- Immunohistochemistry and multiplex immunofluorescence.
- In vivo MAFB depletion studies.
Main Results:
- Recurrent GBM exhibits immune microenvironmental divergence with a distinct CXCL3⁺ TAM population.
- These TAMs display pro-inflammatory profiles and associate with poor survival.
- MAFB is identified as a key regulator of this TAM state, upregulated in recurrent GBM.
- MAFB depletion reduces tumor growth and improves survival in vivo.
Conclusions:
- Significant immune remodeling occurs in primary and recurrent GBM.
- A MAFB-driven CXCL3⁺ macrophage program shapes the recurrent GBM immune landscape.
- This MAFB-macrophage axis presents a potential therapeutic target for GBM microenvironmental reprogramming.
