Defense Date

2022

Document Type

Thesis

Degree Name

Master of Science

Department

Microbiology & Immunology

First Advisor

Masoud Manjili

Abstract

While there have been advancements in treatment options for breast cancer and hepatocellular carcinoma (HCC) there are still many challenges with drug resistance, toxicity and tumor relapse. Serine protease inhibitor, SP16 and its analog A2-5, bind to low density lipoprotein related-receptor protein-1 (LRP-1) leading to pro-survival and anti-inflammatory signaling. Since inflammation is an enabling characteristic in the emerging hallmarks of cancer, modulation of the immunological patterns by SP16 or A2-5 could affect tumorigenesis. To uncover distinct immune modulations during tumor progression and/or inhibition, we performed flow cytometry analysis and 44-plex cytokine/chemokine analysis. In vitro analysis of mouse mammary carcinoma cells (MMC) shows that treatment with A2-5 prior to Adriamycin (ADR) results in a transient inhibition of ADR-induced apoptosis and prevention of MMC regrowth. In vivo analysis of animals on a Western diet (WD) for 16, 20 and 28 weeks showed that treatment during early-stage disease inhibited NAFLD progression and modulated CD4+ T helper patterns. Analysis of animals that had been on a WD for 48 weeks showed that treatment during late-stage disease facilitated a predominant hepatic and splenic CD4+ T regulatory (Treg) pattern without inhibiting HCC. This analysis also revealed a hepatic and splenic loss of CD4+ T cells in the untreated WD group that was alleviated by SP16 treatment and to a lesser degree by A2-5. Further analysis of tumor free and tumor bearing mice, which were pooled regardless of treatment, showed that a balanced CD4+ T helper cell pattern could be host-protective but late treatment failed to prevent HCC likely due to loss of CD4+ T cells and the promotion of Tregs, both of which would inhibit anti-tumor immune responses. Our data suggests that early treatment, either prior to ADR treatment in vitro or during early-stage fatty liver disease in vivo could protect from tumor relapse or tumor progression, respectively.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-6-2022

Available for download on Wednesday, May 05, 2027

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