Successful Immunotherapy For Melanomas Requires Tumor-Infiltrating Monocyte-Derived Dendritic Cells

The recent success of checkpoint blockade therapies has established immunotherapy as one of the most promising treatments for melanoma. Nonetheless, a complete curative response following immunotherapy is observed only in a fraction of the patients. To understand the factors that limit the efficacy of immunotherapies, we established mouse models, which cease to respond to immunotherapies once tumors reach a certain stage. We compared the changes within immune cell populations in the tumor, draining lymph node (DLN) and blood, in responding and non-responding melanoma tumor-bearing mice. Analysis of their immune system revealed that the numbers of tumor-infiltrating dendritic cells (TIDC) drastically decrease with time. We further found that in contrast to the current paradigm, once melanoma is established, TIDC do not migrate into sentinel lymph nodes. Instead, these dendritic cells (DC) undergo local cell death due to excessive phagocytosis of melanoma-derived exosomes. Importantly, we found that TIDC are required to license the cytotoxic activity of tumor CD8⁺ T cells in situ, and in their absence, T cells will not lyse melanoma cells. Overall, this research provides a new insight into the roles of TIDC in tumor, and the means to rescue them from exosome-induced apoptosis, thereby increasing the efficacy of checkpoint blockades, adoptive T cell transfer, as well as other T cell-based immunotherapies.