Research Papers:

Interleukin-15 stimulates natural killer cell-mediated killing of both human pancreatic cancer and stellate cells

Jonas R.M. Van Audenaerde _, Jorrit De Waele, Elly Marcq, Jinthe Van Loenhout, Eva Lion, Johan M.J. Van den Bergh, Ralf Jesenofsky, Atsushi Masamune, Geert Roeyen, Patrick Pauwels, Filip Lardon, Marc Peeters and Evelien L.J. Smits

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Oncotarget. 2017; 8:56968-56979. https://doi.org/10.18632/oncotarget.18185

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Jonas R.M. Van Audenaerde1, Jorrit De Waele1, Elly Marcq1, Jinthe Van Loenhout1, Eva Lion2, Johan M.J. Van den Bergh2, Ralf Jesenofsky3, Atsushi Masamune4, Geert Roeyen5, Patrick Pauwels1,6, Filip Lardon1, Marc Peeters1,7 and Evelien L.J. Smits1,2

1Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

2Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

3Department of Medicine II, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany

4Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan

5Department of Hepatobiliary, Endocrine and Transplantation Surgery, Antwerp University Hospital, Antwerp, Belgium

6Department of Pathology, Antwerp University Hospital, Antwerp, Belgium

7Department of Oncology, Multidisciplinary Oncological Centre Antwerp, Antwerp University Hospital, Antwerp, Belgium

Correspondence to:

Jonas R.M. Van Audenaerde, email: [email protected]

Keywords: natural killer (NK) cells, pancreatic cancer (PDAC), pancreatic stellate cells (PSC), immunotherapy, interleukin-15 (IL-15)

Received: March 14, 2017     Accepted: April 14, 2017     Published: May 25, 2017


Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death in Western countries with a 5-year survival rate below 5%. One of the hallmarks of this cancer is the strong desmoplastic reaction within the tumor microenvironment (TME), orchestrated by activated pancreatic stellate cells (PSC). This results in a functional and mechanical shield which causes resistance to conventional therapies. Aiming to overcome this resistance by tackling the stromal shield, we assessed for the first time the capacity of IL-15 stimulated natural killer (NK) cells to kill PSC and pancreatic cancer cells (PCC). The potency of IL-15 to promote NK cell-mediated killing was evaluated phenotypically and functionally. In addition, NK cell and immune checkpoint ligands on PSC were charted. We demonstrate that IL-15 activated NK cells kill both PCC and PSC lines (range 9-35% and 20-50%, respectively) in a contact-dependent manner and significantly higher as compared to resting NK cells. Improved killing of these pancreatic cell lines is, at least partly, dependent on IL-15 induced upregulation of TIM-3 and NKG2D. Furthermore, we confirm significant killing of primary PSC by IL-15 activated NK cells in an ex vivo autologous system. Screening for potential targets for immunotherapeutic strategies, we demonstrate surface expression of both inhibitory (PD-L1, PD-L2) and activating (MICA/B, ULBPs and Galectin-9) ligands on primary PSC. These data underscore the therapeutic potential of IL-15 to promote NK cell-mediated cytotoxicity as a treatment of pancreatic cancer and provide promising future targets to tackle remaining PSC.

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