The overall survival of a subset of patients with melanoma drastically improved with a type of treatment called immunotherapy, which activates the body’s immune system to fight cancer more effectively. To better understand which patients are most likely to benefit from such treatments it has become increasingly important to identify biomarkers that may be predictive of clinical outcomes. Our project aims to evaluate biomarkers called tertiary lymphoid structures (TLS) to determine their relationship to survival outcomes in patients with melanoma.

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.

Many cancer immunotherapy patients fail to respond or progress after initially experiencing tumor regression. More than 25% of melanomas carry activating mutations in the driver oncogene NRAS. Unlike other genomic variants of melanoma, NRAS mutant patients respond poorly to current immunotherapies and targeted agents; therefore, new therapies are urgently needed. A major gap in knowledge that limits the application of immunotherapy in NRAS mutant cancers is the identification of immunogenic targets selectively expressed by tumor cells and not normal tissues. This proposal seeks to develop new, mechanism-based immunotherapies to target melanoma and other common cancers with specific genetic alterations associated with resistance to current treatments. As part of these studies, new generalizable knowledge will be generated that improves our molecular understanding of how the adaptive immune system can distinguish between normal and transformed tissues.