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

Jonas R.M. Van Audenaerde, Jorrit Dev 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, Evelien L.J. Smits

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)56968-56979
Number of pages12
JournalOncotarget
Volume8
Issue number34
DOIs
Publication statusPublished - 2017

Keywords

  • Immunotherapy
  • Interleukin-15 (IL-15)
  • Natural killer (NK) cells
  • Pancreatic cancer (PDAC)
  • Pancreatic stellate cells (PSC)

ASJC Scopus subject areas

  • Oncology

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