Role and Therapeutic Value of AHR in Inflammatory Macrophages during GBM

项目摘要 神经炎症和免疫抑制对胶质母细胞瘤（GBM）有显著影响。 巨噬细胞浸润脑肿瘤，经历GBM微环境的调节，并促进肿瘤的生长。 抑制肿瘤特异性免疫。通过配体激活的转录因子Aryl的信号传导 碳氢化合物受体（AHR）对免疫应答的调节具有强烈的作用，并且已经 最近参与抑制GBM特异性免疫。然而， AHR调节对GBM的免疫应答，并且AHR作为GBM的治疗靶点的潜力是潜在的。 未知我们发现AHR控制炎症巨噬细胞的募集，也称为胶质瘤- 浸润巨噬细胞转移到GBM此外，我们还发现巨噬细胞中AHR的特异性缺失， 显著减缓GBM生长。基于这些发现，我们假设AHR调节 神经胶质瘤浸润巨噬细胞抑制GBM特异性免疫。在这个项目中，我们建议 研究AHR在GBM浸润巨噬细胞中的作用。我们的具体目标是： 具体目的1：研究AHR控制免疫抑制性巨噬细胞的机制 在GBM。 我们建议1）研究AHR信号在巨噬细胞和小胶质细胞中的差异贡献， GBM免疫抑制; 2）研究巨噬细胞中AHR信号传导的转录作用， GBM中的小胶质细胞。 具体目的2：通过用携带AHR的纳米颗粒靶向AHR来治疗GBM模型 抑制剂的 我们建议1）研究载有AHR抑制剂的纳米颗粒对胶质瘤的影响- 体外浸润巨噬细胞; 2）确定纳米颗粒在实验性GBM中的治疗效果 模型

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.