DOI

https://doi.org/10.25772/7XHM-5D75

Author ORCID Identifier

https://orcid.org/ 0000-0002-1788-9278

Defense Date

2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Clinical and Translational Sciences

First Advisor

Sandro da Rocha

Second Advisor

Douglas Sweet

Third Advisor

Joshua Harrell

Fourth Advisor

Harry Bear

Fifth Advisor

Umesh Desai

Abstract

Breast cancer is the most diagnosed cancer worldwide and the second leading cause of cancer related deaths. About 20% of all breast cancer cases are diagnosed with triple negative breast cancer (TNBC), which has the lowest overall survival rate of any subtype. Because of the lack of hormone receptor expression, chemotherapy is the main treatment option for TNBC patients. Nevertheless, an initial complete response to neoadjuvant treatment is seen in less than 50% of these patients, while many will relapse and develop metastasis leading to a certainty of death. Therefore, a new treatment strategy is necessary. One strategy is to manipulate the immune cells in the tumor microenvironment (TME) of TNBC. Tumor associated macrophages (TAMs) make up to 50% of the cell population in the TME, and their abundance is correlated with worse overall survival in TNBC patients. In this work, we investigated the effectiveness of three macrophage immunotherapies in a primary murine model of TNBC. We demonstrated that treatment with either PLX3397, BLZ945 or all-trans retinoic acid (ATRA) leads to the reduction of the TAM population, while ATRA also reduced the abundance of MDSC in the tumor. This work set the stage for the use of macrophage immunotherapies in combination with other anti-cancer agents to increase the efficacy in treating TNBC patients. We then combined PLX and ATRA with standard of care chemotherapy, doxorubicin (DOX). We showed that in combination with DOX, PLX was still able to reduce the M2-like population, as well as the MDSC population. Furthermore, we showed that combination therapy has a greater efficacy on the reduction of tumor burden than single therapy alone. The use of PLX and ATRA in the treatment of TNBC is very promising and we aim to continue exploring the use of macrophage therapies in combination with standard of care chemotherapy.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

7-23-2022

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Available for download on Thursday, July 22, 2027

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