Author ORCID Identifier

https://orcid.org/0000-0001-6445-4149

Defense Date

2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Microbiology & Immunology

First Advisor

Rebecca Martin

Second Advisor

Harry Bear

Third Advisor

Shawn Wang

Fourth Advisor

Huiping Zhou

Fifth Advisor

Kimberly Jefferson

Abstract

In immune-competent individuals, tumor growth occurs due to a failure of the immune system to recognize and destroy malignant cells. Immune surveillance can be curtailed by the presence of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and T-regulatory cells (Tregs) which both serve to dampen antitumor immunity. These studies utilize a metronomic low-dose therapeutic approach to examine the effects of anticancer drugs against murine breast cancer and the effects on the immune cell compartments. The focus of these studies revolve around the drug guadecitabine (guad), a second-generation DNA methyl-transferase inhibitor (DNMTi). DNMTi’s have been shown to dysregulate the methylation state responsible for gene silencing, which leads to an upregulation of many silenced genes including cancer associated antigens. Guad was initially combined with intratumoral injections of CpG oligodeoxynucleotides, which serve as a danger signal and initiates an immune response against antigens within the treated tumor. Dual treatment of CpG and guad showed decreased tumor burden in treated animals when compared to vehicle controls. Next, guad was combined with low doses of cyclophosphamide (cyp) which is a chemotherapy that has been shown to selectively deplete Tregs at low doses. This drug combination resulted in a depletion in splenic and tumor MDSCs and Tregs, increased CD8+ T cell function, increased tumor associated antigen expression, as well as reduction in tumor size in murine 4T1 and E0771 breast cancer models.

Rights

© Timothy M. Smith Jr.

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-4-2020

Available for download on Wednesday, December 03, 2025

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