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

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

doi:10.18632/oncotarget.18185

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.

Highlights

Pancreatic Ductal Adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate below 5%, rendering it the 4th most common cause of cancer-related death worldwide [1,2,3]
A transwell assay was performed to investigate the need for direct cell-to-cell contact between the stimulated natural killer (NK) cells and the pancreatic cancer cells (PCC) or pancreatic stellate cells (PSC) in order to get killing
Our data show that unstimulated as well as stimulated NK cells need direct cell-to-cell contact with the target cells, indicating that membrane factors play a major role to effectuate a cytotoxic effect of NK cells towards PCC and PSC cells

Summary

Introduction

Pancreatic Ductal Adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate below 5%, rendering it the 4th most common cause of cancer-related death worldwide [1,2,3]. A hallmark of PDAC is the strong desmoplastic reaction which occurs in the tumor microenvironment (TME) resulting in a dense fibrotic/desmoplastic stroma that surrounds the pancreatic cancer cells (PCC) [11,12,13]. This stroma, which can cover more than 50% of the tumor, acts as a mechanical and functional shield causing a diminished delivery of systemically administered anticancer agents due to a high intratumoral pressure and low microvascular density [11,12,13,14,15]. It is strongly believed that (new) treatment options will only be able to exert their full potential provided that this shield is breached [11,12,13,14, 16, 17]

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