CD56bright NK cells exhibit potent antitumor responses following IL-15 priming
Julia A. Wagner, … , Hing C. Wong, Todd A. Fehniger
Julia A. Wagner, … , Hing C. Wong, Todd A. Fehniger
Published October 3, 2017
Citation Information: J Clin Invest. 2017;127(11):4042-4058. https://doi.org/10.1172/JCI90387.
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Research Article Immunology Oncology Article has an altmetric score of 14

CD56bright NK cells exhibit potent antitumor responses following IL-15 priming

Abstract

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 CD56bright subset is involved in immunomodulation. Here, we challenge this paradigm by demonstrating that brief priming with IL-15 markedly enhanced the antitumor response of CD56bright NK cells. Priming improved multiple CD56bright cell functions: degranulation, cytotoxicity, and cytokine production. Primed CD56bright cells from leukemia patients demonstrated enhanced responses to autologous blasts in vitro, and primed CD56bright cells controlled leukemia cells in vivo in a murine xenograft model. Primed CD56bright cells from multiple myeloma (MM) patients displayed superior responses to autologous myeloma targets, and furthermore, CD56bright 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 CD56bright compared with CD56dim NK cells, and blockade of these pathways attenuated antitumor responses. These findings identify CD56bright NK cells as potent antitumor effectors that warrant further investigation as a cancer immunotherapy.

Authors

Julia A. Wagner, Maximillian Rosario, Rizwan Romee, Melissa M. Berrien-Elliott, Stephanie E. Schneider, Jeffrey W. Leong, Ryan P. Sullivan, Brea A. Jewell, Michelle Becker-Hapak, Timothy Schappe, Sara Abdel-Latif, Aaron R. Ireland, Devika Jaishankar, Justin A. King, Ravi Vij, Dennis Clement, Jodie Goodridge, Karl-Johan Malmberg, Hing C. Wong, Todd A. Fehniger

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Figure 1

IL-15–primed human CD56bright NK cells have enhanced responses to tumor target cells.

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IL-15–primed human CD56bright NK cells have ...
(A) Purified NK cells from normal donors underwent short-term (12–16 hours) culture in media alone (control) or media with 5 ng/ml IL-15 (primed). Cells were then washed and triggered with tumor targets. (B) Control or primed purified NK cells were incubated with K562 AML target cells for 6 hours at a 5:1 E:T ratio. Bivariate flow cytometry plots from a representative normal donor show surface CD107a as well as intracellular IFN-γ and TNF following tumor target triggering. Summary data show mean ± SEM percentage of CD107a+, IFN-γ+, and TNF+ NK cells. n = 14 normal donors, 7 independent experiments. (C) Flow-sorted, control or primed CD56bright and CD56dim NK cells were triggered with K562 tumor targets for 6 hours at a 5:1 E:T ratio. Summary data show mean ± SEM percentage of CD107a+, IFN-γ+, and TNF+ NK cells. n = 9 normal donors, 6 independent experiments. Data were compared using a 1-way repeated-measures ANOVA, with Bonferroni’s multiple-comparisons testing of indicated groups. *P < 0.05, **P < 0.01, ***P < 0.001.