Peritoneal NK cells are responsive to IL-15 and percentages are correlated with outcome in advanced ovarian cancer patients
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Janneke S. Hoogstad-van Evert1,2, Ralph J. Maas2,*, Jolien van der Meer2,*, Jeannette Cany2, Sophieke van der Steen1, Joop H. Jansen2, Jeffrey S. Miller3, Ruud Bekkers1, Willemijn Hobo2, Leon Massuger1,* and Harry Dolstra2,*
1Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, The Netherlands
2Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands
3Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
*These authors contributed equally to this work
Janneke S. Hoogstad-van Evert, email: [email protected]
Keywords: natural killer cells; ovarian cancer; IL15; ascites; survival
Received: July 13, 2018 Accepted: September 15, 2018 Published: October 05, 2018
The demonstration that ovarian carcinoma (OC) is an immunogenic disease, opens opportunities to explore immunotherapeutic interventions to improve clinical outcome. In this regard, NK cell based immunotherapy could be promising as it has been demonstrated that OC cells are susceptible to killing by cytokine-stimulated NK cells. Here, we evaluated whether percentage, phenotype, function and IL-15 responsiveness of ascites-derived natural killer (NK) cells is related to progression-free survival (PFS) and overall survival (OS) of advanced stage OC patients. Generally, a lower percentage of NK cells within the lymphocyte fraction was seen in OC ascites (mean 17.4 ± 2.7%) versus benign peritoneal fluids (48.1 ± 6.8%; p < 0.0001). Importantly, a higher CD56+ NK cell percentage in ascites was associated with a better PFS (p = 0.01) and OS (p = 0.002) in OC patients. Furthermore, the functionality of ascites-derived NK cells in terms of CD107a/IFN-γ activity was comparable to that of healthy donor peripheral blood NK cells, and stimulation with monomeric IL-15 or IL-15 superagonist ALT-803 potently improved their reactivity towards tumor cells. By showing that a higher NK cell percentage is related to better outcome in OC patients and NK cell functionality can be boosted by IL-15 receptor stimulation, a part of NK cell immunity in OC is further deciphered to exploit NK cell based immunotherapy.
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