Neuro-inflammation and immunosuppression have a significant impact on glioblastoma (GBM). Macrophages infiltrate brain tumors, undergo modulation by the GBM microenvironment and promote the suppression of tumor-specific immunity. Signaling through the ligand-activated transcription factor Aryl Hydrocarbon Receptor (AHR) has strong effects on the regulation of the immune response and has been recently implicated in the suppression of GBM-specific immunity. However the biological mechanisms by which AHR regulates the immune response to GBM and the potential of AHR as a therapeutic target for GBM are unknown. We found that AHR controls the recruitment of inflammatory macrophages, also called glioma- infiltrating macrophages, to GBM. Moreover, we found that the specific deletion of AHR in macrophages significantly slows GBM growth. Based on these findings, we hypothesize that the AHR modulates glioma-infiltrating macrophages that suppress GBM-specific immunity. In this project, we propose to study the role of AHR in GBM-infiltrating macrophages.
Our specific aims are:
Specific Aim 1 : Investigate the mechanism by which AHR controls immunosuppressive macrophages in GBM. We propose to 1) study the differential contribution of AHR signaling in macrophages and microglia on GBM immunosuppression; 2) investigate the transcriptional effects of AHR signaling in macrophages and microglia in GBM.
Specific Aim 2 : Treatment of a GBM model by targeting AHR with nanoparticles carrying AHR inhibitors. We propose to 1) investigate the effects of nanoparticles loaded with an AHR inhibitor on glioma- infiltrating macrophages in vitro; 2) determine the therapeutic effects of nanoparticles in an experimental GBM model.
Macrophages play an important role in glioblastoma (GBM) progression by suppressing the anti-tumor activity of the immune system. However, the mechanisms of their pathogenicity and pathways regulating them are poorly characterized. We found that the survival of GBM-bearing mice with a specific deletion of the transcription factor aryl hydrocarbon receptor (AHR) in macrophages is significantly improved and this is associated with the reduced infiltration of GBM by inflammatory macrophages. In this project, we propose to study the role of AHR in the control of pathogenic macrophages in GBM progression, and the potential of AHR as a therapeutic target for glioblastoma and other brain tumors.
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