Elucidating the Role of Epigenetic Plasticity in anti-GD2 Immunotherapy Response

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Project Summary (from the funded application) Ganglioside GD2 is expressed on the cell surface of numerous pediatric cancers, including Ewing sarcoma, osteosarcoma, and neuroblastoma. In 2015, FDA approval of the anti-GD2 immunotherapy dinutuximab represented a paradigm shift in the treatment of neuroblastoma by significantly reducing the incidence of tumor recurrence. Despite dinutuximab's success, dinutuximab fails ~30% of neuroblastoma patients. Reports suggest that the degree of surface GD2 expression correlates with clinical response to dinutuximab. However, the cellular mechanisms governing GD2 regulation in tumor cells remain unknown. Correlation of surface GD2 expression with RNA-sequencing in a large cohort of neuroblastoma cell lines revealed that GD2 expression is associated with a mesenchymal epigenetic program. Epithelial-to-Mesenchymal Transition (EMT) has been widely studied in epithelial solid tumors for its purported role in chemoresistance. However, there have been no reports linking an adrenergic-to-mesenchymal transition (AMT) epigenetic program to regulation of surface antigen GD2, making this relationship of intense interest to the neuroblastoma community. In this proposal, AIM 1 will elucidate the relationship between AMT and GD2 expression by rigorously testing the sufficiency and necessity of the neuroblastoma-specific AMT transcription factor PRRX1 to regulate GD2. Further, loss of GD2 expression via AMT will be tested in vitro and in vivo for loss of response to dinutuximab. Aim 2 will evaluate the pathways underlying loss of GD2 expression. Preliminary data suggest that mesenchymal cell lines and tumors express markedly reduced GD3 synthase via epigenetic silencing at the gene promoter. We will evaluate whether AMT directly regulates GD3 synthase, and whether restoration of its expression rescues response to dinutuximab. These findings will directly link epigenetic state to the downregulation of tumor antigen GD2 and response to dinutuximab. Further, these studies may help inform rational combinatorial strategies to enhance anti-GD2 therapies in neuroblastoma, and could provide a framework for future studies in other GD2-expressing pediatric cancers.