Date of Graduation

2014

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Laura F Gibson

Committee Co-Chair

Steven Frisch

Committee Member

Karen H Martin

Committee Member

Michael Ruppert

Committee Member

William Tse

Committee Member

Linda Vona-Davis

Abstract

This dissertation is intentionally broad in scope and describes the conceptual frameworks, research advances, and clinical successes that inspired a therapeutic vision that, in turn, prompted specific RepSox experiments (Jajosky, 2014). The goal of this dissertation is to guide and encourage students interested in engineering anti-cancer immune therapies by providing perspective and suggestions. Chapter I provides background on acute myeloid leukemia (AML), the cancer stem cell (CSC) theory, and the chemical reprogramming tool "RepSox." Chapter II describes how tumor cells passively evade immune recognition and actively suppress immune cells to escape destruction. Immunotherapeutic strategies are described that increase tumor-cell immunogenicity and/or sensitize tumor cells to immune-mediated death. Chapter III reviews immune-cell defects induced by cancer-distorted microenvironments. Tumor cells alter local physical and metabolic conditions and distort surrounding stromal cells in ways that impair infiltrating immune cells and promote cancer progression. Strategies are described that can reverse immune-cell defects and improve anti-tumor immunity. Chapter IV highlights successful cancer immunotherapies, including patient-specific, FDA-approved, and AML leukemic stem cell (LSC)-targeted strategies. These therapies involve antibodies, activated immune cells, and/or immuno-modulatory agents designed to eradicate tumor cells, repair and activate dysfunctional immune cells, and reduce cancer-induced immune suppression in tumor microenvironments. Chapter V describes the features and rationale of a therapeutic vision that, in combination with recent clinical and research findings, guided this project and identified specific technical obstacles. Chapter VI is the published study -- entitled "RepSox slows decay of CD34+ acute myeloid leukemia cells and decreases T cell immunoglobulin mucin-3 expression" -- which describes how RepSox, a "small molecule" reprogramming tool and TGF-beta inhibitor, affects AML cells. The key findings are RepSox (1) slows decay of primary CD34+ AML cells from patients with diverse AML disease, (2) increases CXCL12 and MYC , and (3) accelerates loss of Tim 3, an inhibitory (immune-checkpoint) receptor, from the surface of AML cells. Thus, RepSox may promote in vitro engineering of patient-specific AML LSC-targeted therapies by prolonging survival of primitive CD34+ AML cells and increasing AML-cell immunogenicity via Tim-3 reduction. When envisioning the immunologic synapse between antigen-presenting AML cells and T cells, the actions of RepSox suggest RepSox might promote in vitro T-cell activation against primitive (relapse-causing) AML cells which represent the most problematic therapeutic target. Chapter VII discusses the potential therapeutic applications of these results in the context of AML and other cancers as well as unanswered questions and future research options. For example, the actions of RepSox suggest that its incorporation into pre-existing co-culture methods that exploit TCR agonists may enhance the activation of gammadelta T cells against a patient's primitive AML cells and, thereby, help generate more effective immune-cell therapies. One goal of this dissertation is to encourage students to integrate new findings and conceptual frameworks from immunology, regenerative medicine, and cancer research when deciding which exciting research agendas to pursue.

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