CD56^sup 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 CD56b,ightsubset is involved in immunomodulation. Here, we challenge this paradigm by d...

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Bibliographic Details
Published in:The Journal of clinical investigation 2017-11, Vol.127 (11), p.4042-4058
Main Authors: Wagner, Julia A, Rosario, Maximillian, Romee, Rizwan, Berrien-Elliott, Melissa M, Schneider, Stephanie E, Leong, Jeffrey W, Sullivan, Ryan P, Jewell, Brea A, Becker-Hapak, Michelle, Schappe, Timothy, Abdel-Latif, Sara, Ireland, Aaron R, Jaishankar, Devika, King, Justin A, Vij, Ravi, Clement, Dennis, Goodridge, Jodie, Malmberg, Karl-Johan, Wong, Hing C, Fehniger, Todd A
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
Antitumor activity
Biomedical research
Cancer
Cancer immunotherapy
CD56 antigen
Cytokines
Cytotoxicity
Degranulation
Gene expression
Immune system
Immunomodulation
Immunotherapy
Innate immunity
Interleukin 15
Interleukin 15 receptors
Leukemia
LFA-1 antigen
Lymphocyte receptors
Lymphocytes
Metabolic pathways
Multiple myeloma
Natural killer cells
NKG2 antigen
Signal transduction
Stem cells
T cell receptors
TOR protein
Xenografts
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Summary: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 CD56b,ightsubset is involved in immunomodulation. Here, we challenge this paradigm by demonstrating that brief priming with IL-15 markedly enhanced the antitumor response of CD56b'ight NK cells. Priming improved multiple CD56bright cell functions: degranulation, cytotoxicity, and cytokine production. Primed CD56b'ight 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 CD56b'ight cells from multiple myeloma (MM) patients displayed superior responses to autologous myeloma targets, and furthermore, CD56b'ight 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 CD56b'ightcompared 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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI90387