T Cell Exhaustion in Glioblastoma

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor. Despite standard of care treatment GBM remains universally lethal, demonstrating a significant need for newer treatment strategies such as immunotherapy. Immune checkpoint blockade is a type of immunotherapy which seeks to perpetuate T cell activity by blocking inhibitory immune checkpoints. This strategy has gained FDA approval in several solid tumors, yet has failed in GBM. Severe T cell dysfunction such as T cell exhaustion is a known contributor to failures of immune checkpoint blockade, yet has not been thoroughly described in GBM. In this dissertation, we explore T cell exhaustion as a contributor to immune checkpoint blockade failure in GBM. Chapters 1-3 provide a comprehensive review of several distinct modes of T cell dysfunction in GBM including the importance of T cell exhaustion. In Chapter 4 we demonstrate severe bona fide T cell exhaustion in patients with GBM. In Chapter 5 we explore 4-1BB agonism as a means to prevent T cell exhaustion and thus sensitize GBM to immunotherapeutic strategies. In Chapter 6 we describe the mechanism driving T cell exhaustion and reveal a novel mechanism by which T cell based immunotherapies may recognize and kill tumor cells. In summary, this original work provides several encouraging insights for the development and evaluation of immunotherapeutic strategies, particularly immune checkpoint blockade, in GBM.