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MODULATION OF THE IMMUNE RESPONSE AS A POTENTIAL THERAPEUTIC FOR GLIOBLASTOMA

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title
MODULATION OF THE IMMUNE RESPONSE AS A POTENTIAL THERAPEUTIC FOR GLIOBLASTOMA
author
Sanders, Stephanie Virginia
abstract
Glioblastoma (GBM) is an aggressive, complex and heterogeneous primary brain tumor which is known to be highly immune suppressive. While attempts have been made to utilize immunotherapy to treat GBM, they have not attained desirable clinical success. This is due to several barriers that hamper the use of immunotherapy for GBM treatment. These barriers include the blood-brain barrier (BBB), blood-brain-tumor barrier (BBTB), the immune infiltrate in GBM tumors, and the strong immune suppression both within the GBM tumor microenvironment (TME) and systemically. It is therefore important to understand not only the interactions within the TME of GBM, but also between GBM and the peripheral immune system. A deeper understanding of these interactions will aid in the development of effective treatment strategies that harness the patient’s immune system to treat GBM.In this dissertation, I explore the interactions between GBM and the immune cells within the TME; I also explore the systemic immune environment in GBM patients. I first identify a mechanism by which GBM-associated macrophages (GAM) aid in tumor progression and infiltration into brain parenchyma. I show that GAM over-express aldehyde dehydrogenase 1A2 (ALDH1A2), which catalyzes synthesis of signaling molecule retinoic acid (RA). RA does not appear to affect GBM cells but is able to increase matrix metalloproteinase 9 (MMP-9) activity in GAM; this may promote tumor cell infiltration into surrounding brain. I identify the CD163+ cell population in GBM peripheral blood mononuclear cells (PBMCs) which corresponds to activated macrophages as a possible biomarker that could be used to diagnose and/or monitor the clinical course of GBM. I provide preliminary evidence that GAM may re-enter circulation after tumor education. Additionally, I identify Triggering Receptor expressed on Monocytes (TREM2) as a marker of interest in GBM and other cancer patients. In GBM, I distinguish a population of TREM2+ cells in GBM PBMCs that does not exist in other cancer or normal PBMCs. I propose TREM2 as a potential biomarker for cancer. I present a strategic treatment strategy for harnessing the patient’s immune system to treat GBM. To this end, I design and examine a GBM-targeted combinatorial immune checkpoint inhibitor (ICI), which can be used to overcome immune suppression both locally and systemically and potentiate an immune response against GBM cells. Taken together, this dissertation shows how GBM modulates the patient immune system and presents new targets for diagnosis and/or monitoring along with a strategy for using immunotherapy to treat this aggressive tumor.
subject
ALDH1A2
Glioblastoma
Immune Checkpoint Inhibitor
Immunotherapy
Macrophage
TREM2
contributor
Debinski, Waldemar (committee chair)
Haas, Karen (committee member)
Watabe, Kounosuke (committee member)
Miller, Lance D (committee member)
date
2022-05-24T08:36:21Z (accessioned)
2023-05-23T08:30:12Z (available)
2022 (issued)
degree
Cancer Biology (discipline)
embargo
2023-05-23 (terms)
identifier
http://hdl.handle.net/10339/100788 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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