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10.18632/oncotarget.18185

http://scihub22266oqcxt.onion/10.18632/oncotarget.18185
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suck abstract from ncbi


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pmid28915646
      Oncotarget 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.
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