DOI
https://doi.org/10.25772/DBXH-0E09
Author ORCID Identifier
https://orcid.org/0000-0002-7039-8830
Defense Date
2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Biochemistry
First Advisor
Ross Mikkelsen
Second Advisor
Xiang-Yang Wang
Abstract
Whether the intent is curative or palliative, most cancer patients with solid tumors will undergo some form of radiotherapy during their course of treatment. The vast majority of irradiated cancer cells die via mitotic crisis resulting from DNA damage. One major obstacle for many patients is the phenomenon of acquired radioresistance where, through a series of complex interactions with cells of the tumor stroma, surviving tumor cells acquire traits and behaviors that make them less susceptible to therapy. It has also recently become appreciated that this DNA damage drives an adaptive immune response that is critical for post-treatment tumor control and positive clinical outcomes. However, clinical trials investigating the possibility of synergy between radiotherapy and immunotherapy have been disappointing, calling into question our understanding of this immune response and stimulating multiple investigations into its limiting factors.
Herein, we describe a population of radiation-stimulated extracellular vesicles that have pleotropic effects on the tumor microenvironment, limiting both the cytotoxic effects of RT and its ability to stimulate cells of the immune system. Furthermore, we have identified a novel role for radiation-induced heparan sulfate on the irradiated cancer cell surface as well as on the surface of radiation-induced extracellular vesicles in regulating the character of the irradiated tumor microenvironment. Finally, we have described multiple approaches to limiting the effects of this counter-regulatory phenomenon. This represents a clinical opportunity to enhance the efficacy of both radiotherapy and radiotherapy-immunotherapy combination strategies.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
9-14-2022