KIF9 in Glioblastoma Progression and Immunotherapy

Glioblastoma is one of the most aggressive cancers that are highly malignant with limited surgical approaches due to its spread into surrounding areas of the brain diffusely. We have achieved highly promising preliminary data to believe that the protein KIF9 in the glioblastoma cells mediates the microglia enhanced glioblastoma cell invasion. Knockdown of this KIF9 protein in glioblastoma cells significantly slows down the disease progression of glioblastoma in vivo in multiple glioblastoma mouse models. Meantime, KIF9 has been reported to regulate macrophage activities, which suggests that KIF9 may also play a key role in regulating the macrophage-like microglia cells in the glioblastoma microenvironment. On the other hand, recent clinical trials have confirmed the effectiveness of immunotherapy, especially the immune checkpoint blockade therapy in treating glioblastoma. Thus, in this proposal, we will determine the role of KIF9 in remodeling the glioblastoma microenvironment including the tumor cells themselves and the microglia cells during the cytotoxic CD8+ T cell infiltration based immunotherapy. In detail, we will scrutinize the role of KIF9 in regulating glioblastoma cell spreading ex vivo and in vitro in our developed 3D spheroid cell co-culture and co- invasion system. We will also determine the role of KIF9 in regulating cell proliferation, cell-to-cell adhesion, inter-cell signaling, protein transport, etc. in both the tumor cells and the microglia cells (Objective 1). By employing multiple glioblastoma mouse models, we will further determine the role of KIF9 in glioblastoma invasion and proliferation and how it mediates the crosstalk between glioblastoma cells and microglia cells in vivo (Objective 2). Meanwhile, recent clinical trial results have reported very promising data on glioblastoma immunotherapy. Thus, to pave our way for the future “KIF9 blockade + immunotherapy” combo therapy to treat glioblastoma, we will further determine the role of KIF9 in regulating the glioblastoma microenvironment remodeling during immunotherapy in vivo, specifically the checkpoint blockade immunotherapy (Objective 3). The major goal of this study is to propose, evaluate and compare the Monotherapy of “KIF9 blockade” and the Combo therapy of “KIF9 blockade + immunotherapy” in treating glioblastoma.