Membrane anchored immune stimulatory proteins enhance anti-tumor immunity in breast cancer models Open Access

Bozeman, Erica N. (2013)

Permanent URL: https://etd.library.emory.edu/concern/etds/t435gd795?locale=en
Published

Abstract

Despite significant advances being made in the cancer field, breast cancer accounts for millions of deaths worldwide. Multiple strategies have been employed to combat this deadly disease such as chemotherapy, radiation therapy and various forms of immunotherapies. And while many are capable of reducing tumor burden or inducing tumor-specific immune responses, most are hampered by the development of therapeutic resistance over time. Our studies sought to investigate the efficacy of cellular based vaccines that were genetically modified to express glycosyl phosphatidylinositol immune stimulatory molecules (GPI-ISMs). The choice of ISMs, B7-1, GPI-IL-2 and GPI-IL-12, all play a critical role in the activation and cytotoxic capabilities of cellular immune responses, primarily mediated by T- and NK-cells. We demonstrate using multiple breast cancer models that the co-expression of B7-1 and GPI-IL-12 is highly effective at significantly reducing overall tumor burden and tumor incidence in prophylactic as well as therapeutic settings. In the non-metastatic, 4TO7 model, cellular vaccines expressing this combination of ISMs led to a significant reduction in myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs) locally within the tumor microenvironment as well as in the periphery. While in the HER-2 positive, D2F2/E2 model such tumor inhibition was accompanied by a reduction in HER-2 specific humoral immunity and an enhancement in HER-2 specific cellular immunity. Moreover in both models, long-lasting memory responses were induced following cellular vaccination with GPI-ISMs as evident by protection from secondary tumor challenges.

To further enhance the anti-tumor immunity that was induced following vaccination, combinatorial approaches with the cytotoxic agent Ukrain and an immunological blockade, anti-PD-L1 were investigated. The tumor-specific cytotoxicity of Ukrain minimally enhanced tumor inhibition in the 4TO7 model relative to vaccination alone while PD-L1 blockade served as an effective adjuvant in the D2F2/E2 model. Taken together, cellular vaccines expressing GPI-ISMs proved to be an effective approach in the battle against tumor development in multiple breast cancer models though the manipulation of immune suppression and the promotion of antigen-specific cellular immunity.

Table of Contents

Abstract

Acknowledgements

List of Figures

Chapter I: Introduction …………………………………………………………………............................................................................................1

Chapter II: Expression of membrane anchored cytokines and B7-1 alters tumor microenvironment and

induces protective anti-tumor immunity in a murine breast cancer model....……………....................................................................30

Chapter III: Irradiated cellular vaccines expressing B7-1 and GPI-cytokines promote the induction of tumor-

specific cytotoxic activity and protective anti-tumor responses in a HER-2 positive murine tumor model.... ......................................60

Chapter IV: Ukrain, a plant-derived semi-synthetic compound, exerts antitumor effects against murine and

human breast cancer and induce protective anti-tumor immunity in mice………………………...............................................................94

Chapter V: Discussion…………………………………………………………………............................................................................................131

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