The Role of Lineage-specific Transcription Factors in Regulating Anti-tumor Immune Responses in Melanoma
Abstract
Melanoma is a deadly form of skin cancer that arises from the malignant transformation of melanocytic skin cells. Its incidence is increasing every year, and in2021 it is predicted that 7,180 people will die from this disease in the United States. Scientific efforts over the past few decades have greatly advanced our understanding of melanoma biology and tumor immunology, leading to the development of new therapeutic options for melanoma patients. Targeting immune checkpoint proteins reinvigorates anti-tumor immune responses, resulting in clinical benefit. While these advancements have led to the FDA-approval of treatments that improve overall patient survival and response durability, many melanoma tumors are refractory to current treatments or acquire secondary resistance following an initial response. The tumor intrinsic signaling pathways that contribute to immune evasion and prevent tumors from responding to immunotherapeutic interventions are incompletely understood. My long term goal is to develop new strategies for the treatment of melanoma patients. In this thesis, I performed studies aimed at gaining a more comprehensive understanding of the oncogenic drivers of this disease and potential immunological targets.In embryonic development, the lineage-specific transcription factors FOXD3 andSOX10 play key roles in the differentiation of melanocytes from neural crest precursors. In melanoma, these proteins regulate multiple gene targets. Previous studies have demonstrated a link between embryonic transcription factors and immune regulation. Thus, I hypothesized that lineage-specific transcription factors regulate immune-related targets in melanoma, and investigated the role of FOXD3 and SOX10 in modulating antitumor immune responses. I observed that FOXD3 represses expression of the immune checkpoint protein VISTA, and provided evidence that VISTA is expressed on melanoma cells. Furthermore, I showed that FDA-approved inhibitors of MAPK signaling reduce VISTA expression levels, implicating VISTA as a potential therapeutic target in melanoma. To study the role of SOX10 in melanoma, I utilized a CRISPR/Cas9 approach to knockout Sox10 expression and identified HVEM and CEACAM1 as immune checkpoint targets of SOX10. In comparison to parental cells, Sox10-knockout cells formed tumors less frequently in vivo, and this effect was partially dependent on the presence of CD8+ T cells. Furthermore, Sox10 ablation rendered melanoma cells sensitive to T cell killing and the induction of inflammatory cell death by T cell-secreted cytokines.The findings presented here identify novel regulatory connections between lineage-specific transcription factors and anti-tumor immune responses. These studies advance our knowledge of oncogenic signaling pathways in melanoma and contribute to a broader understanding of the complex interactions between tumor and immune cells.
Subject Area
Oncology
Recommended Citation
Rosenbaum, Sheera, "The Role of Lineage-specific Transcription Factors in Regulating Anti-tumor Immune Responses in Melanoma" (2021). ProQuest ETD Collection - Thomas Jefferson University. AAI28414737.
https://jdc.jefferson.edu/dissertations/AAI28414737
