Characterization of Glioblastoma and T Cell Migration in Brain Tissue

Abstract

Glioblastoma (GBM) is an aggressive malignant brain tumor with extremely low 5-year survival rates. One key characteristic of the disease is the ability of glioblastoma cells to migrate rapidly and spread throughout healthy brain tissue. To develop treatments that effectively target cell migration, it is important to understand the fundamental mechanism driving cell migration in brain tissue. In the first part of this dissertation, we utilized confocal imaging to measure traction dynamics and migration speeds of glioblastoma cells in mouse organotypic brain slices to identify that the cells are using a motor-clutch mode of migration. In addition, both integrins and CD44, as well as myosin motors, were found to play an important role in constituting the adhesive clutch. In developing a treatment that targets migration of glioblastoma cells, it is critical to take into account how this could impact T cell migration and the resulting ability of T cells to kill cancer cells. A hallmark of glioblastoma is the suppression of the immune response, allowing the tumor to grow and spread faster, and infiltration of cytotoxic CD8+ T cells into the tumor has been shown to be an important indicator of disease progression and survival. In the second part of this dissertation, we use mouse organotypic brain slices co-cultured with CD8+ T cells to image migrating CD8+ T cells in healthy brain tissue in response to cell migration targeting drugs and antibodies. We find an increase in migration speed in response to targeting CD44, which is a critical deviation between cancer cell and T cell phenotype, implicating CD44 as a potential target for improving glioma outcomes by slowing cancer cell migration and speeding up CD8+ T cells.