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2017 ; 8
(34
): 56968-56979
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Interleukin-15 stimulates natural killer cell-mediated killing of both human
pancreatic cancer and stellate cells
#MMPMID28915646
Van Audenaerde JRM
; De Waele J
; Marcq E
; Van Loenhout J
; Lion E
; Van den Bergh JMJ
; Jesenofsky R
; Masamune A
; Roeyen G
; Pauwels P
; Lardon F
; Peeters M
; Smits ELJ
Oncotarget
2017[Aug]; 8
(34
): 56968-56979
PMID28915646
show ga
Pancreatic ductal adenocarcinoma (PDAC) is the 4(th) 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.