CD4+T cells play a role in melanoma immunosurveillance in mice and humans. The precise underlying anti-tumoral mechanism of CD4+T cells remains a subject of debate. Discrepancies in findings could be attributed to the heterogeneity of the CD4+T cell lineage and thus their sensitivities to differences in tumor microenvironments. By using a novel orthotopic murine model, that closely resembles the location and progression of melanoma in humans, we are attempting to disentangle the uncertainty surrounding the mechanism of melanoma immunosurveillance by CD4+ T cells. In this model we have shown that antigen-specific CD4+T cells are able to migrate into the skin and control epicutaneously-lodged melanoma cells. We found that MHC-II expression by melanoma cells increases infiltration of CD4+T cells into the tumor and can enhance immune control. However, our results indicate that MHC-II expression by melanoma cells is not a prerequisite for the anti-tumoral function of CD4+T cells and thus this project seeks to elucidate the antigen-presenting cells involved in presentation of tumor antigens to CD4+ T cells. Finally, we explore the intrinsic tumor cell-killing mechanism of CD4+T cells as well as their cross-talk with other immune cells to mediate melanoma control.