Preclinical Investigations of the Immune Microenvironment in Glioblastoma Público
Herting, Cameron J. (Fall 2019)
Abstract
Glioblastoma is the most common and malignant primary brain tumor with a dismal survival of just over one year following diagnosis even with the most aggressive treatment regimens. Limited advances have been made with respect to development of efficacious anti-neoplastic therapies to treat this deadly disease over the past fifty years. Part of the limited success stems from the models used for preclinical investigation that neglect the molecular characteristics of human glioblastoma as well as the immune microenvironment. Herein, I present novel subtype-specific murine models of glioblastoma that leverage the driver mutations uncovered through molecular analysis of human patient samples. I establish that the murine models display gene expression profiles and microenvironmental compositions that closely mirror what is observed in the human disease. Notably, I show that tumor-associated macrophages are present in these murine tumors at similar levels to what is observed in human tumors. I demonstrate that these models respond differently to anti-neoplastic therapies used to combat glioblastoma and suggest that molecular profiling should be employed clinically to inform on treatment plans. Using these models, I then investigate the role that tumor-associated macrophages play in the development of cerebral edema in glioblastoma with a focus on interleukin-1 signaling. My in vitro, ex vivo, and in vivo results establish interleukin-1 as a downstream target of dexamethasone; the drug currently employed to combat cerebral edema in glioblastoma. Additionally, I provide evidence that bone marrow-derived macrophages and not microglia are the primary producers of interleukin-1 in the tumor microenvironment. I demonstrate that genetic ablation of interleukin-1 signaling is able to phenocopy dexamethasone treatment with respect to inhibition of bone marrow-derived macrophage chemotaxis and inhibition of edema development in vivo. Finally, I reveal that genetic or pharmacological inhibition of interleukin-1 signaling in vivo does not impair response to radiation therapy that is seen following dexamethasone treatment. In total, these results suggest that specific inhibition of interleukin-1 signaling offers an attractive alternative to dexamethasone treatment.
Table of Contents
Chapter 1: Introduction..................... 1
1.1 Glioblastoma Historical Perspective and Current Status....... 2
1.2 Clinical and Epidemiological Characteristics of Glioblastoma...... 4
1.3 Histological and Molecular Classification........................................ 9
1.4 The Glioblastoma Tumor Microenvironment............................ 11
1.5 Therapeutic Interventions in Glioblastoma...................................... 22
1.6 Rationale and Goals of this Project.................................................. 31
Chapter 2: Subtype-Specific Mouse Modeling of Glioblastoma.............. 33
2.1 Introduction................................. 34
2.2 Materials and Methods............. 39
2.3 Results........................................... 45
2.4 Discussion.................................... 79
Chapter 3: The Role of Interleukin-1 in the Formation of Glioblastoma-Associated Cerebral Edema........... 89
3.1 Introduction................................. 90
3.2 Materials and Methods............. 95
3.3 Results......................................... 105
3.4 Discussion.................................. 140
Chapter 4: Conclusions and Future Directions......................................... 145
4.1 Conclusions................................ 146
4.2 Future Directions..................... 149
References........................................ 158
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