Investigating why large tumors often fail to respond to immunotherapy, Santana-Magal et al. found that in established murine melanomas, tumor-infiltrating DCs (TIDCs), most of which were monocyte-derived, did not migrate to sentinel lymph nodes. TIDCs were found to be essential for licensing cytotoxic activity by CD8+ TILs, however, TIDCs in large tumors underwent apoptosis over time due to excessive phagocytosis of lysosomes. In ACT studies, agonist anti-CD40 enhanced the numbers and viability of MoDCs, improving antitumor efficacy. Analysis of patient data showed that activated MoDCs in tumors correlated with improved survival.
Contributed by Lauren Hitchings
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.