CD56^bright NK cells exhibit potent antitumor responses following IL-15 priming

NK cells, lymphocytes of the innate immune system, are important for defense against infectious pathogens and cancer. Classically, the CD56dim NK cell subset is thought to mediate antitumor responses, whereas the CD56^bright subset is involved in immunomodulation. Here, we challenge this paradigm by demonstrating that brief priming with IL-15 markedly enhanced the antitumor response of CD56^bright NK cells. Priming improved multiple CD56^bright cell functions: degranulation, cytotoxicity, and cytokine production. Primed CD56^bright cells from leukemia patients demonstrated enhanced responses to autologous blasts in vitro, and primed CD56^bright cells controlled leukemia cells in vivo in a murine xenograft model. Primed CD56^bright cells from multiple myeloma (MM) patients displayed superior responses to autologous myeloma targets, and furthermore, CD56^bright NK cells from MM patients primed with the IL-15 receptor agonist ALT-803 in vivo displayed enhanced ex vivo functional responses to MM targets. Effector mechanisms contributing to IL-15-based priming included improved cytotoxic protein expression, target cell conjugation, and LFA-1-, CD2-, and NKG2D-dependent activation of NK cells. Finally, IL-15 robustly stimulated the PI3K/Akt/mTOR and MEK/ERK pathways in CD56^bright compared with CD56dim NK cells, and blockade of these pathways attenuated antitumor responses. These findings identify CD56^bright NK cells as potent antitumor effectors that warrant further investigation as a cancer immunotherapy.