Date of Award

Summer 2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program/Concentration

Biomedical Sciences - Bioelectrical Science

Committee Director

Stephen J. Beebe

Committee Director

Siqi Guo

Committee Member

Christopher Osgood

Committee Member

Woong-Ki Kim

Abstract

Nanopulse treatment (NPT) is a high-power electric engineering modality that has been shown to be an effective local tumor treatment approach in multiple cancer models. Our previous studies on the orthotopic 4T1-luc breast cancer model demonstrated that NPT ablated local tumors. The treatment consequently conferred protection against a second live tumor challenge and minimized spontaneous metastasis. This study aims to understand how NPT mounts a potent immune response in a predominantly immunosuppressive tumor.

NPT changed the local and systemic dynamics of immunosuppressive cells by significantly reducing the numbers of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) that contribute to the dominant immunosuppressive environment in the 4T1-luc mouse breast cancer model. The Treg suppression capacity and activation markers, including 4-1BB and TGFβ, were diminished post-treatment, and the Treg activation profile shifted from a predominantly activated (CD44+CD62L-) to a naïve (CD44-CD62L+) profile. Furthermore, we observed an increase in apoptosis among Tregs and TAMs followed by a concomitant M1-macrophage polarization of the surviving TAMs. Meanwhile, a continuing rise in the effector T cell (Teff) / Treg ratio and among resident memory CD8 T cells hinted at the expansion of antitumor specific cytotoxic T cells. Overall, these findings suggest that NPT is a potent tumor microenvironment (TME) modifier that can effectively reverse the tumor’s immunosuppressive barrier by decreasing MDSCs, TAMs and functionally suppressive Tregs. Thus, the TME modification by NPT confers cytotoxic T cell function and immune memory formation contributing to the tumor challenge rejection and reduction in metastasis risk.

Future studies will investigate the underlying mechanisms of NPT-induced T cell immunity by determining the changes it creates among Treg and Teff T cell receptor (TCR) clonality in both mice and humans. Control studies on human blood indicated that peripheral Tregs are predominantly polyclonal in nature among healthy donors. Overall, these findings on NPT-induced immunity can help develop novel immunotherapeutic approaches to effectively treat poorly immunogenic cancers, such as breast and pancreatic cancers, that are largely resistant to current systemic immunotherapies.

DOI

10.25777/csve-7081

ISBN

9798460434473

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