Both helper CD4 T cells and killer CD8 T cells are known to be involved in immune responses to cancer. Helper CD4 T cells assist immune responses to cancer by enhancing the function of killer CD8 T cells as well as innate immune cells and antibody producing B cells. Growing large numbers of T cells from a patient and re-infusing them can increase the number of tumor specific T cells and can benefit melanoma patients who have failed other treatments in particular variant melanomas, such as mucosal melanomas, that are less immunogenic. This proposal is focused on understanding how helper CD4 T cells function when used as a cellular therapy and trying to develop ways to engineer these cells to be more potent, using a mouse model of melanoma. The first part of the proposal is understanding how infused CD4 T cells function when the interactions between the T cells and their target antigens are weaker, such as is often the case in variant melanomas such as mucosal melanoma, and when they have to see their antigen targets indirectly through other immune cells in the tumor, as this is often the case in many human melanomas. The second part of the proposal is to engineer CD4 T cells to target additional inflammatory signals to tumors, in hopes that this will lead to greater activation of immune cells and destruction of the tumors. The results from these studies in mice will inform the design of clinical trials we are currently planning using CD4 T cells in human melanoma.