TY - JOUR
T1 - Interleukin-15 stimulates natural killer cell-mediated killing of both human pancreatic cancer and stellate cells
AU - Van Audenaerde, Jonas R.M.
AU - Dev Waele, Jorrit
AU - Marcq, Elly
AU - Van Loenhout, Jinthe
AU - Lion, Eva
AU - Van den Bergh, Johan M.J.
AU - Jesenofsky, Ralf
AU - Masamune, Atsushi
AU - Roeyen, Geert
AU - Pauwels, Patrick
AU - Lardon, Filip
AU - Peeters, Marc
AU - Smits, Evelien L.J.
N1 - Funding Information:
are research fellows of the Research Foundation Flanders (fellowship numbers 1S32316N and 1121016N, respectively). Elly Marcq is a research fellow of the Flanders Innovation & Entrepreneurship (fellowship number 141433). Jinthe Van Loenhout is supported by a research grant of the University of Antwerp (BOF). Johan MJ Van den Bergh received an Emmanual van der Schueren fellowship from Kom op tegen Kanker. Eva Lion is supported by research grants from Kom op tegen Kanker and the foundation against Cancer (‘Stichting tegen Kanker’; STK2014-155). This work was performed with the support of the Flemish Gastroenterology Association and the University Foundation of Belgium. We also want to express our special gratitude to Mr. Willy Floren and the Vereycken family for their kind gifts which enabled us to perform this research project.
Publisher Copyright:
© Van Audenaerde et al.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Immunotherapy
KW - Interleukin-15 (IL-15)
KW - Natural killer (NK) cells
KW - Pancreatic cancer (PDAC)
KW - Pancreatic stellate cells (PSC)
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UR - http://www.scopus.com/inward/citedby.url?scp=85029078024&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.18185
DO - 10.18632/oncotarget.18185
M3 - Article
AN - SCOPUS:85029078024
VL - 8
SP - 56968
EP - 56979
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 34
ER -