Date of Award

12-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Genetics, Genomics, and Informatics

Research Advisor

Kevin Freeman, Ph.D.

Committee

David Ashbrook, PhD; Evan Glazer, MD; Liza Makowski, PhD; Lawrence Pfeffer, PhD

Keywords

cancer; pediatric cancer; immunotherapy; epigenetic therapy

Abstract

Neuroblastoma (NB) is a highly aggressive, heterogeneous disease that arises from the sympathetic nervous system (SNS) and originates from neural crest cells (NCCs) (1). NB is the most common extracranial cancer in pediatric accounts for 15% of pediatric cancer deaths (2). This high mortality rate is the result of the metastatic, immune evasive, and treatment resistant characteristics of the disease (3). It has been proposed that NB arises from blocks in differentiation during development, resulting in a mixture of two distinct cell types within the tumor: mesenchymal and adrenergic (Figure 1.1) (4,5). The adrenergic cell type is more differentiated, and patients that exhibit more of this cell type have greater treatment success. The mesenchymal cell type is more stem like and is associated with the metastatic, immune evasive, and treatment resistant traits of NB (6,7). Because NB is considered a disease of development, many therapeutic strategies targeting epigenetic factors are being investigated in pre-clinical and clinical trials. Our work is currently focused on interrogating how the loss of ARID1A, a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, affects NB’s oncogenesis and the immune evasive effects of the mesenchymal cell type. The successful completion of this project will 1) determine if ARID1A loss is a critical component for immune suppression by collapsing inflammatory signaling, and 2) examine three epigenetic therapies to develop better strategies for increasing immune infiltration and targets to immunotherapies common for NB. NB patient samples have been sequenced extensively (8), and it has been reported that there is a low median exonic mutation frequency as well as few recurrently mutated genes (9). This does not allow for many potential therapeutic targets, and even multimodal therapy can be unsuccessful and lead to relapse. Many recent studies focus on the chromosomal instability events that take place in NB and aberrant epigenetic regulation during NCC development (10). 1p36 loss of heterozygosity (LOH) occurs in around 29% of high-risk NB patients which has been linked to the treatment resistant (1-6) and immunologically suppressed phenotype. Previously, the Freeman lab established that one of the main tumor suppressors located in this area is ARID1A (5,11). Recent data reports that ARID1A has a role in initiating inflammatory signaling in adult cancers by opening areas of chromatin thereby enabling the transcription of Th1 signaling genes (13-19), but this immune impairment has not been sufficiently investigated in NB. NB is considered a cold tumor, a designation characterized by a lack of infiltrating CD8+ T cells, NK cells, and NK-T cells in the tumor microenvironment; low MHC-I expression; and lack of tumor antigens (20-22). These characteristics further decrease therapeutic options for patients (6, 11), and the few options that are available can lead to severe toxicities and adverse events. Disialoganglioside GD2 therapy is one form of immunotherapy for NB (11), which has only a 40% efficacy rate when paired with cytokine stimulation in NB patients (9). Strategies to improve treatment outcomes with anti-GD2 therapy are essential to limiting adverse reactions to the treatment and increase efficacy. One such strategy is combining common immunotherapies with epigenetic therapies. By overcoming aberrant epigenetic regulation, inflammatory sensing can increase leading to greater immunotherapy treatment outcomes. As stated previously, ARID1A loss has been linked in adult cancers to a decrease in Th1 signaling responses, specifically inflammatory signals, which lead to a lack of immune infiltration by NK cells and CD8+ T cells (28-30). Previously, the Freeman lab established that aberrant epigenetic regulation including ARID1A loss, not MYCN amplification, is a cause for cellular immaturity, developmental blocks, and cell state plasticity in NB; a

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

DOI

10.21007/aetd.cghs.2024.0016

Additional Files
2024-016-Watson-AETD-DOA.pdf (212 kB)
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