Barry et al. show that in mice with melanoma, intratumoral NK cell expression (but not T cell expression) of Flt3l controls the levels of intratumoral CD103+BDCA-3+ cDC1s, a subset of DCs uniquely capable of intratumoral stimulation of cytotoxic T cells. NK cells appeared to control the frequency of cDC1s in the tumor via frequent and stable interactions between the two cell types. In patients with melanoma, NK cell levels correlated with both FLT3L expression and intratumoral cDC1 levels. Levels of NK cells and intratumoral cDC1s correlated with increased survival and predicted response to anti-PD-1 therapy.
Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T cells and driving immune responses against cancer. Understanding the mechanisms that regulate their abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma, SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in tumor through production of FLT3L. Although anti-PD-1 'checkpoint' immunotherapy for cancer largely targets T cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as an excellent prognostic tool for T cell-directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis as a target for new therapies.