Targeting RNA splicing machinery to enhance anti-tumor immunity in neuroblastoma
Mentor Name: William Weiss
Neuroblastoma is a prevalent extracranial solid tumor in childhood originating from the adrenal gland and paraspinal nerve tissue. Approximately 50% of high-risk tumors in neuroblastoma exhibit the amplification of proto-oncogene, which is associated with a poor prognosis and an immunosuppressive tumor microenvironment. Our laboratory has developed a unique, non-germline genetically engineered mouse model (Mycn-nGEMM) driven by Mycn, where Mycn is introduced into embryonic trunk neural crest cells from C57BL/6J mice. Tumor-derived cell lines from these mice exhibit robust growth in C57BL/6J hosts, displaying immunosuppression comparable to that observed in MYCN-amplified human tumors. In our unpublished findings, we noted that RNA splicing inhibitors upregulate MHC-I-related gene expression and enhance the presence of tumor-infiltrating lymphocytes in this model. Our hypothesis posits that targeting the RNA splicing machinery could enhance anti-tumor immunity. In this project, we will 1) treat Mycn-nGEMM cells with RNA splicing inhibitors, followed by co-culturing with cytotoxic CD8+T cells to assess various aspects such as cell viability, cell death, and immune-related markers for both cell types, 2) examine the tumor immune microenvironment of Mycn-nGEMM tumors, and 3) inject cells into C57BL/6J mice to establish Mycn-nGEMM tumors, administrate RNA splicing inhibitors, and harvest tumor tissue, aftewards examining the tumor immune microenvironment of Mycn-nGEMM tumors and resecting tumor for analysis to examine immune cell profiles.
