The role of TSPO in T cell immune control of glioblastoma

TSPO经常在胶质母细胞瘤（GBM）（一种高度侵袭性但不可治愈的脑肿瘤）中过表达，并且在炎症条件下通过TNF诱导。GBM中TSPO的表达与WHO分级、胶质瘤细胞增殖和预后不良呈正相关。然而，TSPO在GBM进展中的功能作用远未被理解。我们建议，TSPO调节GBM的免疫控制。由于TSPO对GBM的抗肿瘤T细胞应答的作用和TSPO免疫调节作用的机制迄今尚未研究，因此该项目侧重于TSPO在胶质母细胞瘤特异性细胞毒性效应T细胞排斥人GBM细胞期间的作用。TSPO通过其天然配体的活化可以阻断白细胞介素（IL）8的产生，白细胞介素（IL）8控制活性氧（ROS）水平并导致针对促凋亡炎症刺激的保护。另一方面，TSPO介导神经类固醇的产生，其可诱导炎性细胞因子如IL 6、肿瘤坏死因子（TNF）或IL 1。这些细胞因子对效应T细胞活性发挥不同的作用，因此可能在GBM中肿瘤免疫排斥反应的调节中发挥关键但复杂的作用。因此，我们想要研究在GBM发展和治疗期间TSPO表达在治疗抗性和免疫保护方面的后果。通过遗传基因沉默和用合成配体对TSPO活性的药理学调节，我们产生了初步数据，表明一方面TSPO在GBM细胞中T细胞诱导的细胞凋亡的调节中起剂量依赖性作用，另一方面在协调肿瘤特异性T细胞的效应子功能中起作用。这些发现表明，TSPO的药理学靶向可能代表胶质母细胞瘤免疫治疗的潜在治疗选择。该项目建立在使用TSPO配体的遗传操作和药理学干预的基础上，使用了大量的亚型解剖的代表性人类GBM组织样本组（参见项目A1）和来自患者的GBM祖细胞及其自体肿瘤抗原特异性T细胞系的原代培养物。我们将建立GBM祖细胞中TSPO与T细胞排斥的总体相关性，确定TSPO如何调节GBM的炎症反应，研究TSPO在T细胞诱导的GBM祖细胞凋亡过程中的作用，表征TSPO对T细胞对GBM细胞的反应的调节，研究TSPO对GBM浸润免疫细胞亚群的影响。因此，本项目不仅将发展TSPO参与GBM免疫控制的机制假说，而且还将探索TSPO在GBM免疫控制中的潜力。用于GBM免疫治疗的药理学TSPO调节。

TSPO is frequently overexpressed in glioblastoma (GBM), a highly aggressive yet incurable brain tumor, and is induced through TNF under conditions of inflammation. TSPO expression in GBMs positively correlates with WHO grade, glioma cell proliferation and poor prognosis of patients. However, the functional role of TSPO in GBM progression is far from being understood. We propose that TSPO regulates the immune control of GBM. Because neither the role of TSPO for anti-tumor T cell responses against GBM nor mechanisms underlying the immune-regulatory role of TSPO have been studied so far, the project focuses on the role of TSPO during the rejection of human GBM cells by glioblastoma-specific cytotoxic effector T cells. TSPO activation by its natural ligands can block the production of interleukin (IL) 8 which controls reactive oxygen species (ROS) levels and results in protection against pro-apoptotic inflammatory stimuli. On the other hand, TSPO mediates the production of neurosteroids which can induce inflammatory cytokines such as IL6, tumor necrosis factor (TNF) or IL1. Such cytokines exert differential effects on effector T cell activity and may therefore play a critical but complex role in the regulation of tumor-immune rejection in GBM. Therefore, we want to study the consequences of TSPO expression during GBM development and treatment both with regard to treatment resistance and immune protection. By genetic gene silencing and pharmacological modulation of TSPO activity with synthetic ligands we generated preliminary data suggesting that on the one hand TSPO plays a dose dependent role in the regulation of T cell induced apoptosis in GBM cells and on the other hand in orchestrating effector functions of tumor specific T cells. These findings suggest that pharmacological targeting of TSPO could represent a potential therapeutic option for immunotherapy of glioblastoma. The project builds up on genetic manipulation and pharmacological interventions with TSPO ligands using a large subtype-dissected representative panel of human GBM tissue samples (see project A1) and primary cultures of GBM progenitor cells from patients and their autologous tumor antigen specific T cell lines. We will establish the overall relevance of TSPO in GBM progenitor cells for their rejection by T cells, determine how TSPO modulates the inflammatory response of GBM, investigate the role of TSPO during T cell-induced apoptosis in GBM progenitor cells, characterize the regulation of T cell response against GBM cells by TSPO, and study the impact of TSPO on GBM infiltrating immune cell subsets.This project will thus not only develop mechanistic hypotheses of TSPO involvement in GBM immune control but also explore the potential of pharmacological TSPO modulation for GBM immunotherapy.