Author ORCID Identifier

https://orcid.org/0000-0002-4106-8330

Date of Graduation

12-2020

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Jennifer A. Wargo, M.D., M.M.Sci.

Committee Member

Michael A. Davies, M.D., Ph.D.

Committee Member

Richard E. Davis, M.D.

Committee Member

Giulio F. Draetta, M.D., Ph.D.

Committee Member

Padmanee Sharma, M.D., Ph.D.

Abstract

Melanoma is an aggressive malignancy of melanocytes with historically poor outcomes. Melanoma therapy has improved markedly over the past decade with advances in molecularly targeted agents and immunotherapies. Immune checkpoint inhibitors achieve T-cell mediated anti-tumor efficacy by blocking engagement of inhibitory checkpoints on T-cells to overcome immunosuppressive signals from tumor cells and the broader microenvironment. Despite these advances, there are a significant proportion of patients who do not benefit from existing immunotherapy strategies making it a priority to identify and target the mechanisms that confer resistance to therapy. We demonstrate that microRNAs are accurate markers of microenvironment composition with prognostic value for overall survival in melanoma. We also identified networks of microRNA and mRNA expression in melanoma tissue and melanoma cell lines that are associated with previously identified melanoma transcriptomic subsets. These microRNA networks encompass several key oncogenic processes including epithelial to mesenchymal transition and expression of melanoma specific transcription factors including MITF. Furthermore, investigation of these microRNAs in a cohort of PD-1 inhibitor treated melanoma patients identified a survival benefit in patients whose melanomas had high expression of miR-100-5p and miR-125b-5p. These findings indicate that microRNA regulation of gene expression in melanoma is relevant to melanoma biology, composition of the immune microenvironment and outcomes to PD-1 checkpoint blockade.

Keywords

Melanoma, Immunotherapy, MicroRNA

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