Role and Therapeutic Value of AHR in Inflammatory Macrophages during GBM

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PROJECT SUMMARY 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.