Mentor Name: Leonard Zon

While immunotherapies have revolutionized the treatment options for adult melanoma, they have remained largely ineffective for treating pediatric melanomas. Defining the biological basis for this disparity is therefore of major therapeutic interest, as understanding the mechanism of resistance and immune evasion may provide the foundation for improved immunotherapeutic strategies for solid pediatric tumors. The zebrafish provides a powerful model organism to investigate pediatric melanoma. The Zon laboratory has established well documented MiniCoopR models of NRAS-driven and ZCCHC8-ROS1-driven pediatric melanoma. These two models are distinct subtypes of pediatric melanoma with differing therapeutic challenging. Utilizing these models, we will generate such tumors in various immune cell reporter lines to visualize immune cell dynamics, especially CD8+ T cells, macrophages, and NK cells. High-resolution imaging will enable us to characterize the immune composition in the tumor microenvironment of pediatric melanoma and directly compare it with adult melanoma. In a recent publication, the Zon lab has identified pocket-like structures on the melanoma surface, called CRATERs, which are characterized by elevated antigen presentation and location of prolonged interaction of CD8+ T cells with melanoma cells. Since CRATERs have been described as structures of active tumor killing, they might be a useful diagnostic indicator for immunotherapy success. We will investigate whether analogous structures are present in the pediatric melanoma model and whether their presence or absence contributes to immunotherapy efficacy in pediatric melanoma.