Targeting Melanoma with iNKT-Enhanced Dendritic Cell Immunotherapy

Melanoma is the 5th leading cause of cancer with 100,000 new cases annually in the United States. Though some melanomas carry mutations that can be targeted with drugs, these do not provide lasting remissions. Furthermore, a large number of T-regulatory cells, M2-like macrophages, and myeloid-derived suppressor cells infiltrate tumors and directly suppress tumor-targeting immune cells. We believe that the dendritic cell (DCs), a type of white blood cell, can overcome these immunosuppressive signals. DCs present pieces of cancer called antigens to train immune cells. By injecting large numbers of DCs directly into tumors, we have shown in clinical trials with aggressive HER2-positive breast cancer patients that, before chemotherapy and surgery, these injections can shrink multiple tumors throughout the body with few side effects. This response correlates with significant increases in immune cells and decreases in immunosuppressive cells in the tumor. We believe this DC therapy can work across all cancer types when paired with a lipid antigen called a-GalCer, which is recognized by invariant natural killer T cells (iNKTs). iNKT cells are universally present in all people. Although they have been shown to enhance immunosuppressive myeloid cells, preliminary work suggests that a-GalCer DCs can train iNKT cells to convert immunosuppressive cells into supportive cells. In mouse models of melanoma, blocking the interaction between DCs and iNKT cells prevents the DC immunotherapy from working as well. By using a series of direct coculture experiments, flow cytometry, and RNA-sequencing, we are seeking to understand how iNKT cells work with DCs to regress tumors, understand how iNKT cells subsequently change immunosuppressive cells into supportive cells, and test whether the combination of iNKT cells with DCs can create a therapy that can reduce or even replace the need for toxic chemotherapy.