The role of TSPO in T cell immune control of glioblastoma

点击翻译按钮获取中文摘要

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.