Author ORCID Identifier

https://orcid.org/0000-0001-7706-5206

Date Available

7-23-2024

Year of Publication

2024

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Graduate School

Department/School/Program

Behavioral Science

Advisor

Dr. Jill Kolesar

Abstract

Ovarian cancer, recognized for its high lethality and resistance to conventional immunotherapies, mandates innovative strategies to confront its intricate challenges. The tumor microenvironment (TME), orchestrated by tumor-associated macrophages (TAMs), assumes a pivotal role in disease progression, rendering TAMs an appealing therapeutic target. This study endeavors to explore the prospect of repolarizing TAMs from a protumor M2 phenotype to an antitumor M1 state, employing M1 macrophage-derived vesicles (MEVs) as a groundbreaking immunotherapeutic approach.

The primary objective is to investigate the capacity of M1 MEVs to repolarize M2 macrophages in vitro towards an anti-tumor M1-like phenotype. By inducing human macrophages to adopt an M1 phenotype and generating MEVs, the study seeks to uncover their potential to reshape the immunosuppressive TME towards a more favorable antitumor state.

Concurrently, the research addresses the crucial issue of cancer-targeting properties for selective chemotherapy delivery, utilizing cisplatin-encapsulated MEVs (cisMEVs). This dual-focused approach aims to enhance therapeutic precision while mitigating off-target effects, imperative for overcoming prevalent resistance mechanisms in ovarian cancer. The comprehensive assessments of cisMEVs encompass cell viability, dsDNA damage, and TAM repolarization, providing a nuanced understanding of their multifaceted impact on the complex ovarian cancer microenvironment.

Additionally, the study evaluates the in vivo localization of murine-derived M1 MEVs within ovarian cancer tumor xenografts. The promising outcomes in both in vitro and in vivo settings underscore the potential clinical significance of MEVs in redefining the ovarian cancer therapeutic landscape.

In conclusion, this study unveils the potential of MEVs as an innovative and multifunctional avenue for ovarian cancer immunotherapy. By repolarizing TAMs and enhancing cancer cell targeting, MEVs offer a promising strategy to navigate the challenges posed by the immunosuppressive TME in ovarian cancer, paving the way for future therapeutic advancements and improved patient outcomes.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2024.309

Funding Information

This study was supported by the National Institutes of Health T32: Oncology Research Training for Surgeon Scientists Post-Doctoral Fellowship grant (2020 – 2022) Principal Investigator: B. Mark Evers, T32 CA160003.

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