Date of Completion

4-25-2019

Embargo Period

4-24-2019

Keywords

Cytomegalovirus, Melanoma, Cancer Immunotherapy

Major Advisor

Kamal Khanna, PhD

Associate Advisor

Lynn Puddington, PhD

Associate Advisor

Robert Clark, MD

Associate Advisor

Louise McCullough, MD, PhD

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Cytomegalovirus (CMV) is a ubiquitous herpes virus that generates a unique T cell response, characterized by the maintenance of a high frequency of virus-specific T cells over the lifetime of the host. This prolonged T cell response makes CMV an attractive vaccine platform. Our lab has previously generated a recombinant murine CMV (MCMV) expressing a modified melanoma antigen, MCMVgp100KGP, which protects mice from tumor challenge. In Chapter 3 of this current study, we hypothesized that CMV vectors expressing multiple tumor antigens would be more effective vaccines in the treatment of melanoma. However, our data show that novel MCMV vectors expressing two melanoma antigens do not delay tumor growth compared to MCMVgp100KGP, highlighting the difficulty in targeting shared tumor antigens.

In Chapter 4, we sought to improve the efficacy of MCMVgp100KGP by combination immunotherapy. Herein, we show that adoptive cell therapy enhances the antitumor effects of MCMV-based vaccines. MCMVgp100KGP maintains adoptively transferred cells at higher frequencies than an acute viral vector, but fails to eradicate established tumors. In response to vaccination with MCMVgp100KGP, several immunosuppressive molecules including PD-L1, Qa-1b, and IDO1 are upregulated within the tumor microenvironment, suggesting several mechanisms of tumor resistance. Surprisingly, blockade of these molecules did not improve the antitumor activity of MCMVgp100KGP vaccination. This data further calls into question the reliability of PD-L1, Qa-1b, and IDO1 expression as predictive markers for response to therapies targeting these pathways. In the context of vaccination, these molecules may serve as indicators of effective vaccination rather than predictive biomarkers for combination immunotherapy.

Lastly, this study also identifies a novel population of CD169+ tumor associated macrophages (TAMs). In Chapter 5, we characterize a population of CD169+ TAMs found within the melanoma tumor tissue. This population expresses higher levels of MHCII and CD80, suggesting a potential to prime antitumor T cells. Preliminary data also suggests that CD169+ TAMs may preferentially phagocytose tumor cell fragments directly within the tumor bed. Future work will determine the role of these TAMs in priming antitumor T cells and regulating antitumor immunity.

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