CD56bright NK cells exhibit potent antitumor responses following IL-15 priming
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
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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Research Article Immunology Oncology

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 8

IL-15 more robustly activates the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK pathways in CD56bright NK cells.

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IL-15 more robustly activates the PI3K/Akt/mTOR and ...
(A) Flow cytometry plot shows gating strategy for CD56bright versus CD56dim NK cells based on relative CD56 and CD16 expression. (B) IL-15Rβ expression was assessed via flow cytometry on purified NK cells. Representative data show percentage IL-15Rβ–positive cells and IL-15Rβ MFI on freshly purified CD56bright and CD56dim NK cells. n = 8 normal donors, 3 independent experiments. (C) Summary data show pAkt and pERK MFI in unstimulated CD56bright and CD56dim NK cells. n = 7 normal donors, 3 independent experiments. (D–F) Purified NK cells were incubated with 5 ng/ml IL-15 for 30 minutes (pSTAT5) or 2 hours (pAkt and pERK) then assessed for signaling molecule phosphorylation. Representative histograms show per-cell expression of pSTAT5 (D), pAkt (E), and pERK (F) in IL-15–stimulated (shaded gray) versus unstimulated (gray line) CD56bright or CD56dim NK cells. Summary data show mean ± SEM fold increase of phosphorylated molecule MFI in IL-15–stimulated CD56bright or CD56dim NK cells relative to unstimulated cells. n = 7 normal donors, 3 independent experiments. Data were compared using a paired Student’s t test. *P < 0.05, ***P < 0.001.