Wagner et al. used IL-15 or the IL-15R agonist ALT-803 to prime human CD56bright NK cells (from either healthy donors or multiple myeloma [MM] patients) ex vivo, inducing a strong anti-tumor response to hematological tumor targets in vitro and in leukemic NSG mice. CD56bright NK cells isolated from MM patients treated with ALT-803 in a clinical trial demonstrated enhanced, albeit transient, functionality. Anti-tumor effects were attributed to enhanced expression of cytotoxic and adhesion molecules.
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.
Author Info: (1) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (2) Department of Medicine, Division of Oncology, Washington U
Author Info: (1) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (2) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (3) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (4) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (5) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (6) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (7) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (8) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (9) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (10) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (11) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (12) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (13) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (14) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (15) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. (16) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway. The KG Jebsen Centre for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Norway. (17) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway. (18) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway. The KG Jebsen Centre for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Norway. Centre for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (19) Altor BioScience, Miramar, Florida, USA. (20) Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.
