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

Available for download on Monday, September 13, 2027

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