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 patients. To identify what factors limit the efficacy of
immunotherapies, we established mouse models that cease to respond to
immunotherapies once their
tumors exceed a certain stage. Analysis of the immune systems of the organisms revealed that the numbers of
tumor-infiltrating dendritic cells (TIDC) drastically decreased with time. Further, in contrast to the current paradigm, once
melanoma was established, TIDC did not migrate into sentinel lymph nodes. Instead, they underwent local cell death due to excessive phagocytosis of lysosomes. Importantly, TIDC were required to license the cytotoxic activity of
tumor CD8+ T cells, and in their absence, T cells did not lyse
melanoma cells. Our results offer a paradigm shift regarding the role of TIDC and a framework to increase the efficacy of
immunotherapies. SIGNIFICANCE: This work redefines the role of monocyte-derived dendritic cells in
melanoma and provides a novel strategy to increase the efficacy of T-cell-based
immunotherapies in nonresponding individuals. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/10/1942/F1.large.jpg.