Role of FAP-positive cells in immune response to irradiated glioblastoma

点击翻译按钮获取中文摘要

PROJECT SUMMARY Glioblastoma (GBM) is a devastating brain tumor disease with a median overall survival of approximately 15 months. GBM patients die because of the constant ability of GBM to acquire resistance mechanisms against anti-cancer therapies, therefore leading to an inevitable tumor recurrence. A. Radiation therapy (RT) is a pivotal modality for improving overall survival of GBM. However, GBM invar- iably recurs, which suggests that RT is eliciting or exacerbating mechanisms of resistance in GBM. Identifying and overcoming the contributing factors involved in GBM resistance is a major challenge. Immunosup- pression exerted by cells expressing fibroblast activating protein-alpha (FAP) can account for the lack of immu- nogenicity of irradiated GBM. FAP is a type II transmembrane serine protease that is heavily expressed in the stroma of multiple solid tumors and has thus become a marker to identify cancer-cell associated fibroblasts (CAFs). While our knowledge about CAFs or CAF-like cells in GBM is limited. Few studies reported the presence of glioblastoma-associated stromal cells (GASCs) that share phenotypic and functional properties of CAFs de- scribed in the stroma of carcinomas, but none investigated the role of this cell type in respect to immunosup- pression of irradiated GBM. Our preliminary analyses suggest that FAP+ cells represent a major immune sup- pressive subset in irradiated GBM. Specifically, we demonstrate that (1) FAP+ cells with fibroblastic morphology surround GBM tumor, (2) FAP is mostly expressed by tumor infiltrating myeloid cells in vivo, (3) in vitro irradiation of GBM and microglia cells enhances FAP together with PD-L1 and PD-L2 expressions and (4) targeting FAP increases the recruitment of CD8+ T cells and CD11c+ into GBM in vivo. This work shed light on FAP+ cells as a master regulator of anti- immunity and identifies FAP targeting as a new strategy to immune reactivity of irra- diated GBM. In this application, we propose to test the novel and innovative hypothesis that FAP+ cells represent a major immune suppressive subset that provide the means to suppress anti-tumor immunity in GBM. Successful completion of this work will (1) uncover the role of FAP+ cells in immunosuppression of irradiated GBM and (2) provide evidence for a novel therapeutic intervention that will break through immune resistance of irradiated GBM by targeting FAP.