Understanding the tumor microenvironment in glioblastoma for the development of focused therapies

Abstract

Glioblastoma (GB), a grade IV glioma, is the most aggressive brain tumor, with an incidence of 2-5 cases per 100,000 people per year in the United States. Despite advancements in treatment, the median survival for patients remains approximately 17 months. GB is resistant to therapies effective for other cancers, partly due to the blood-brain barrier and its heterogeneous nature. GB tumors contain diverse transcriptional subtypes of neoplastic cells that mimic neurodevelopmental lineages and adapt to their local environments, driving the aggressive behavior of GB. The tumor microenvironment (TME), encompassing both cancerous and non-cancerous cells such as blood vessels, the extracellular matrix, and various immune cells, plays a critical role in GB progression. The complex TME contributes to GB’s resistance to radiation and chemotherapy, fostering a “cold” tumor state with a low immunogenic profile that hinders effective immune responses. The first part of this thesis focuses on the role of astrocytes, microglia, and cytotoxic T cells within the TME, emphasizing the communication between astrocytes and GB cells through extracellular vesicles. The second part explores three potential therapeutic strategies aimed at reducing tumor growth, offering insights into promising avenues for treatment.