Role and Therapeutic Value of AHR in Inflammatory Macrophages during GBM

项目总结 神经炎症和免疫抑制对胶质母细胞瘤(GBM)的发生有重要影响。 巨噬细胞侵袭脑肿瘤，受到基底膜微环境的调节，促进肿瘤的发生。 抑制肿瘤特异性免疫。通过配体激活的转录因子芳基传递信号 碳氢化合物受体(AHR)在免疫反应的调节中具有很强的作用，一直以来 最近被认为与抑制GBM特异性免疫有关。然而，通过这些生物机制 AHR对GBM免疫应答的调节作用及其作为GBM治疗靶点的可能性 未知。我们发现，AHR控制炎性巨噬细胞的募集，也称为胶质瘤- 巨噬细胞渗入基底膜。此外，我们还发现，巨噬细胞中AHR的特异性缺失 显著减缓了GBM的增长。基于这些发现，我们假设AHR调节 胶质瘤-浸润性巨噬细胞，抑制GBM特异性免疫。在这个项目中，我们建议 研究AHR在基底膜浸润性巨噬细胞中的作用。我们的具体目标是： 特异性目标1：研究AHR控制免疫抑制巨噬细胞的机制 单位为GBM。 我们建议1)研究AHR信号在巨噬细胞和小胶质细胞中的不同作用。 GbM免疫抑制；2)研究AHR信号在巨噬细胞和 基底膜的小胶质细胞。 特定目标2：靶向AHR的携带AHR纳米粒治疗GBM模型 抑制剂。 我们建议1)研究负载AHR抑制剂的纳米颗粒对脑胶质瘤的影响。 2)检测纳米粒对实验性基底细胞瘤的治疗作用 模特。

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.