IL-2/IL-15 signaling induces NK cell production of FLT3LG which augments anti-PD-1 immunotherapy

Natural killer (NK) cells play a critical role in anti-cancer immunity through their direct cytotoxicity and production of cytokines, such as Flt3L. NK cell production of Flt3L controls conventional type I dendritic cell (cDC1) abundance in the tumor and promotes protective immune responses. Here, we show that NK cell production of Flt3l in the tumor is regulated by activation, and that activation by IL-2 and IL-15 uniquely induces Flt3L expression in NK cells. IL-2 signaling in NK cells leads to more Flt3L production, increased cDC1 abundance in the tumor, and increased activity of anti-PD-1 immunotherapy in melanoma. Further, NK cell subsets differentially regulate Flt3L in the tumor, with CD11b–CD27+ NK cells in mouse tumors enriched for IL-2-family signaling and upregulating Flt3l upon activation. Further, human CD56brightCD16– NK cells more strongly correlate with cDC1 and FLT3LG levels than other NK cell subsets across multiple human melanoma datasets and cancer indications. This mechanistic insight into NK cell regulation of FLT3LG and control of the NK cell-cDC1 axis provides insights and novel strategies for the development of more effective cancer immunotherapies.