Graduation Date

Spring 5-10-2025

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Cancer Research

First Advisor

Dalia El-Gamal, M.Sc., Ph.D.

Second Advisor

Joyce Solheim, Ph.D.

Third Advisor

Grinu Mathew, Ph.D.

Fourth Advisor

Maher Abdalla, Ph.D.

Abstract

Myeloid-derived suppressor cells (MDSCs) contribute to immune suppression observed in chronic lymphocytic leukemia (CLL). MDSCs are immature myeloid cells hijacked during development and further reprogrammed by the tumor microenvironment to harbor immune-suppressive capacities and inhibit T-cell functions. Bromodomain and extraterminal domain (BET) protein—including BRD4—are epigenetic modulators that regulate important genes implicated in CLL pathogenesis and tumor microenvironment interaction. Previously, our lab has investigated how the novel BET-inhibitor OPN-51107 (OPN5) prevents CLL disease expansion, modulates T-cell immune function, and alters gene expression related to MDSCs. In turn, we hypothesized that BET proteins, especially BRD4, directly contribute to the regulation of MDSC functions; therefore, pharmacological inhibition of BRD4 will alleviate MDSC-mediated immune suppression in CLL. Through the course of this project, we demonstrated that BRD4 is upregulated in MDSCs isolated from Eu-TCL1 mice (a murine model of CLL), and those MDSCs are more immune-suppressive as compared to MDSCs from wild-type counterparts. Furthermore, we demonstrated that ex vivo OPN5 treatment of MDSCs isolated from leukemic mice reverses their immune-suppressive capacity. Finally, utilizing an aggressive adoptive transfer Eu-TCL1 murine model, we demonstrated that OPN5 treatment slows CLL disease progression and modulates immune cell populations. Specifically, OPN5 resulted in phenotypic and functional changes in MDSCs, resulting in decreased immune-inhibitory receptors and attenuated MDSC-mediated T-cell immune suppression as compared to vehicle-treated mice. Altogether, these data support BET proteins as a viable target in MDSCs and BET inhibition as a potential therapeutic approach to reverse MDSC-mediated immune suppression in the context of CLL.

Comments

2025 Copyright, the authors

Download

Available for download on Saturday, May 01, 2027

Share

COinS