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 [CD56.sup.dim] NK cell subset is thought to mediate antitumor responses, whereas the [CD56.sup.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.sup.bright] NK cells. Priming improved multiple [CD56.sup.bright] cell functions: degranulation, cytotoxicity, and cytokine production. Primed [CD56.sup.bright] cells from leukemia patients demonstrated enhanced responses to autologous blasts in vitro, and primed [CD56.sup.bright] cells controlled leukemia cells in vivo in a murine xenograft model. Primed [CD56.sup.bright] cells from multiple myeloma (MM) patients displayed superior responses to autologous myeloma targets, and furthermore, CD56b'igl,t 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.sup.bright] compared with [CD56.sup.dim] NK cells, and blockade of these pathways attenuated antitumor responses. These findings identify [CD56.sup.bright] NK cells as potent antitumor effectors that warrant further investigation as a cancer immunotherapy.