Protective mechanisms called “immune evasion” thus making it difficult for immunotherapies to be fully effective and to lead to complete cure. These mechanisms have only recently been recognized to involve suppression of immune responses by activating negative regulatory pathways (also called checkpoints) that are associated with immune homeostasis, or by adopting features that enable tumor cells to actively escape detection. Current therapeutic strategies are aimed at mobilizing the host’s immune system to eliminate tumor cells by stimulation of the anti-tumor cell response of cytotoxic T cells and inhibition of tumor induced immune cell paralysis. Given that only a minority of patients respond to these therapies, we need to further understand the interaction between melanoma cells and the immune system. Conventional approaches to investigate human cancer are limited by the fact that only end stage tumor cells are transplanted into host animals that are immune deficient, which eliminates the possibility to investigate any anti-tumor immune reaction or immune evasion. We propose to establish an experimental model system that allows the study of initiation, progression and manifestation of human melanoma in immune competent host animals. The approach is based on generating human-mouse neural crest (NC) chimeras. NC cells emerge from the neural tube at gastrulation and generate a wide variety of lineages including the entire pigment system, as well as the autonomous nervous system. Thus, the melanocyte cells that give rise to melanoma are derived from NC cells. We have shown that in utero injection of human NC cells into the gastrulating embryo generates postnatal chimeras with coat pigmentation derived from the human donor cells. More importantly, we showed that human neuroblastoma, a childhood tumor derived from the NC, develop in human–mouse NC chimeras when the donor NC cells express engineered neuroblastoma relevant oncogenes. Most relevant for this proposal, these tumors develop in immune-competent mice and are invaded by host cytotoxic CD8 T cells as well as T-Regs, which inhibit the cytotoxic action of the T cells. These results provide proof of principle that human-mouse NC chimeras allow the investigation of immune reaction and immune evasion of human tumor cells in an in vivo model system. A major impediment to the accurate study of cancer progression and immune evasion is the lack of animal models representative of human disease. In this project we propose to generate human-mouse NC chimeras which carry melanoma relevant oncogenes in the donor NC cells. This platform will help understanding the ways in which melanoma cells are able to evade the immune system, allow identifying novel targets and testing novel strategies for immunotherapies.