Characterizing and Arresting Bone Marrow T-cell Sequestration in the Setting of Glioblastoma and Other Intracranial Tumors

Initiation and maintenance of a productive anti-tumor immune response requires a functional T-cell repertoire. Disruptions to T-cell function contribute to tumor immune escape, and to failure of the anti-tumor immune response in cancer patients. T-cell dysfunction is particularly severe in certain types of cancers such as glioblastoma (GBM), which is the most common primary malignant brain tumor in adults and is extremely lethal. Despite near universal confinement to the intracranial compartment, GBM frequently depletes both the number and function of systemic T-cells. A lack of understanding of the mechanisms underlying T-cell dysfunction poses challenges to the goal of developing appropriate and meaningful therapeutic platforms. Currently available treatments, including immunotherapies, for GBM and other intracranial diseases have proven ineffective in part because of underlying T-cell dysfunction. Thus, there is an unmet need for therapies that effectively address T-cell dysfunction. In this dissertation, we explore bone marrow T-cell sequestration, a novel mode of T-cell dysfunction present in GBM and other intracranial tumors.

Chapter 1 provides a comprehensive review of the epidemiology, clinical manifestation and diagnosis, and current standard of care for GBM. Chapter 2 outlines immunotherapeutic strategies under investigation for GBM. Chapter 3 describes the fading notion of traditional brain immune privilege but provides the current understanding of how the brain remains immunologically distinct. In Chapter 4, we explore bone marrow T-cell sequestration, and how this mechanism is usurped by GBM and other intracranial tumors to prevent anti-tumor efficacy of T-cell based immunotherapeutic modalities. In Chapter 5, we propose β-arrestin 2 (BARR2) depletion as a strategy to overcome bone marrow T-cell sequestration. In summary, this original work provides encouraging insights for the development of strategies to enhance anti-tumor efficacy of T-cell based immunotherapy for GBM, reversal of bone marrow T-cell sequestration.