Across various soluble and cell-bound signals, Avanessian and van den Bijgaart et al. identified IL-2 and IL-15 to be uniquely capable of inducing Flt3L production by immunomodulatory NK cells. In vitro, IL-2- or IL-15-pretreated NK cells improved the maintenance of cDC1s in a Flt3L-dependent manner. In vivo, i.t. injected IL-2-treated NK cells increased cDC1 numbers in the TME and augmented the efficacy of anti-PD-1 treatment over the effects of IL-18-treated NK cells. In human melanoma and other cancer samples, more CD56brightCD16- NK cells and IL-2-family signaling correlated with increased FLT3LG expression and cDC1 counts.
Contributed by Ute Burkhardt
ABSTRACT: 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 induced Flt3L expression in NK cells. In melanoma, IL-2 signaling in NK cells led to increased Flt3L production, which boosted cDC1 abundance in the tumor and improved anti-PD-1 immunotherapy response. Further, NK cell subsets differentially regulated Flt3L in the tumor, with CD11b-CD27+ NK cells in mouse tumors enriched for IL-2-family signaling and upregulated Flt3l upon activation. Consistently, human CD56brightCD16- NK cells more strongly correlated with cDC1 and FLT3LG expression than other NK cell subsets across multiple human melanoma datasets and cancer indications. This mechanistic study of NK cell regulation of FLT3LG and control of the NK cell-cDC1 axis provides insights and strategies for the development of more effective cancer immunotherapies.
Author Info: (1) Fred Hutchinson Cancer Center, United States. (2) Fred Hutchinson Cancer Center, United States. (3) Fred Hutchinson Cancer Center, Seattle, WA, United States. (4) Massachusetts
Author Info: (1) Fred Hutchinson Cancer Center, United States. (2) Fred Hutchinson Cancer Center, United States. (3) Fred Hutchinson Cancer Center, Seattle, WA, United States. (4) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (5) Fred Hutchinson Cancer Center, Seattle, WA, United States. (6) Fred Hutchinson Cancer Center, Seattle, United States. (7) Fred Hutchinson Cancer Center, United States. (8) Fred Hutchinson Cancer Center, Seattle, WA, United States. (9) Fred Hutchinson Cancer Center, Seattle, France. (10) Fred Hutchinson Cancer Center, Seattle, WA, United States.
