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Published on: November 28, 2015
ZBTB18 regulates cytokine expression and affects microglia/macrophage recruitment and commitment in glioblastoma
Roberto Ferrarese1,2, Kevin Joseph1, Geoffroy Andrieux3
1Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.
Abstract:
Glioma associated macrophages/microglia (GAMs) play an important role in glioblastoma (GBM) progression, due to their massive recruitment to the tumor site and polarization to a tumor promoting phenotype. GAMs secrete a variety of cytokines, which facilitate tumor cell growth and invasion, and prevent other immune cells from mounting an immune response against the tumor. Here, we demonstrate that zinc finger and BTB containing domain 18 (ZBTB18), a transcriptional repressor with tumor suppressive function in glioblastoma, impairs the production of key cytokines, which function as chemoattractant for GAMs. Consistently, we observe a reduced migration of GAMs when ZBTB18 is expressed by glioblastoma cells, both in cell culture and in vivo experiments. Moreover, RNA sequencing analysis shows that the presence of ZBTB18 in glioblastoma cells alters the commitment of conditioned microglia, suggesting the loss of the immune-suppressive phenotype and the acquisition of pro-inflammatory features. Thus, therapeutic approaches to increase ZBTB18 expression in GBM cells could represent an effective adjuvant to immune therapy in GBM.
Insights
Increasing zinc finger and BTB containing domain 18 (ZBTB18) in glioblastoma (GBM) cells reduces glioma-associated macrophages/microglia (GAMs) recruitment and promotes anti-tumor immunity. This suggests ZBTB18 as a potential therapeutic target for GBM.
Area of Science:
- Neuro-oncology
- Immunology
- Molecular Biology
Background:
- Glioma-associated macrophages/microglia (GAMs) promote glioblastoma (GBM) progression by supporting tumor growth and invasion.
- GAMs create an immunosuppressive tumor microenvironment, hindering anti-tumor immune responses.
Purpose of the Study:
- To investigate the role of zinc finger and BTB containing domain 18 (ZBTB18) in regulating GAMs and its potential as a therapeutic target in GBM.
Main Methods:
- Utilized cell culture and in vivo models to assess GAM migration.
- Performed RNA sequencing analysis on glioblastoma cells expressing ZBTB18.
- Investigated the impact of ZBTB18 on cytokine production and microglial phenotype.
Main Results:
- ZBTB18 expression in GBM cells significantly impairs the production of chemoattractant cytokines for GAMs.
- Reduced GAM migration was observed in both cell culture and in vivo experiments when ZBTB18 was present.
- RNA sequencing revealed that ZBTB18 alters microglia towards a pro-inflammatory phenotype, reducing immune suppression.
Conclusions:
- ZBTB18 acts as a tumor suppressor in GBM by inhibiting GAM recruitment and promoting an anti-tumor immune response.
- Therapeutic strategies aimed at increasing ZBTB18 expression in GBM could enhance the efficacy of immunotherapy for glioblastoma.
