"Using RNA-Sequencing to Explore Mechanistic Markers, New Therapeutics," by Naomi Lydia Rapier-Sharman

Abstract

Cancer and autoimmune diseases both impose a substantial healthcare burden on the US and world populations. In 2016, there were over 17 million cases of cancer, leading to nearly nine million deaths. Additionally, autoimmune diseases cause substantial mortality and morbidity and are present in 3-5% of the general population. Despite the increased attention scientists now give diseases that are impacted by immune imbalance, we have yet to find regimens to treat the core cause(s) of tissue dysfunction without drastically decreasing the quality of life for many patients with either cancer or autoimmune disease. For instance, anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy often aid patients to remission, but at the cost of their immune functionality as they acquire B-cell aplasia caused by on-target/off-cancer toxicity. This B-cell aplasia and other immune-related adverse events that are associated with anti-CD19 CAR T-cell treatment highlights the need for better therapeutic targets and more precise knowledge of the underlying immune response mechanisms. We argue that current approaches used to investigate and treat diseases and conditions associated with immune imbalance need to be updated. We propose viewing immune imbalance as a whole entity, rather than as separate events, to reduce at least a subset of the problems that have plagued the field for years. Our hypothesis for this study is that identifying mechanistic markers and intracellular signaling pathways that play a role in immune imbalance can facilitate the prediction of potential therapeutics. To test this hypothesis, we demonstrated in two tissue systems—breast tissue and B-cells--and three distinct diseases—Triple-Negative Breast Cancer (TNBC), B-Cell Non-Hodgkin’s Lymphoma (hereafter B-cell lymphoma), and Systemic Lupus Erythematosus (SLE or lupus)—that an immune-centric perspective enables discovery of cellular mechanisms that may be leveraged for diagnostics or treatment. We began with a bulk RNA-sequencing (RNA-seq) differential gene expression study focusing on TNBC, which afflicts 2.3 million individuals (predominantly women) worldwide each year and is often refractory to treatment, causing 685,000 deaths annually. We followed our TNBC analysis with a similar study examining B-cell lymphoma, a blood cancer for which anti-CD19 CAR T-cell therapy is currently approved. Finally, we conducted a novel study designed to compare cancer to an autoimmune disease in a single tissue type, reflecting the immune balance dynamics affecting the relevant tissue. To do this, we compared B-cells from lymphoma and lupus to identify the shared underlying or contrasting mechanisms, indicative of tissue dysfunction and/or chronic inflammation, as well as genes demonstrating opposite directionality in their dysregulation. We believe that both the shared and the contrasting mechanisms between B-cell lymphoma and lupus will better characterize the internal immune functionality of these immune-mediated diseases, revealing additional targetable mechanisms and augmenting the development and availability of immune-balanced treatments. We propose that this approach is an effective starting point for examining the mechanisms of immune imbalance, which has not been addressed at this scale before.

Degree

PhD

College and Department

Life Sciences; Microbiology and Molecular Biology

Rights

https://lib.byu.edu/about/copyright/

Date Submitted

2025-01-24

Document Type

Dissertation

Handle

http://hdl.lib.byu.edu/1877/etd13514

Keywords

RNA-sequencing, secondary analysis, immune imbalance, transcriptomics, immunology, cancer, autoimmune disease, treatment options, drug repurposing, biomarkers, mechanistic markers

Language

english

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