Natural killer cells and their therapeutic role in pancreatic cancer: A systematic review

Abstract

Pancreatic cancer is among the three deadliest cancers worldwide with the lowest 5-year survival of all cancers. Despite all efforts, therapeutic improvements have barely been made over the last decade. Even recent highly promising targeted and immunotherapeutic approaches did not live up to their expectations. Therefore, other horizons have to be explored. Natural Killer (NK) cells are gaining more and more interest as a highly attractive target for cancer immunotherapies, both as pharmaceutical target and for cell therapies. In this systematic review we summarise the pathophysiological adaptions of NK cells in pancreatic cancer and highlight possible (future) therapeutic NK cell-related targets. Furthermore, an extensive overview of recent therapeutic approaches with an effect on NK cells is given, including cytokine-based, viro- and bacteriotherapy and cell therapy. We also discuss ongoing clinical trials that might influence NK cells. In conclusion, although several issues regarding NK cells in pancreatic cancer remain unsolved and need further investigation, extensive evidence is already provided that support NK cell oriented approaches in pancreatic cancer.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is among the three most deadliest cancers in Western countries, recently overtaking breast cancer (Dreyer, Chang, Bailey, and Biankin, 2017). The 5-year survival of 7% has barely changed in 50 years and is stated as the worst of any cancer type (Dreyer et al., 2017; Evan et al., 2017). PDAC has proven to be an extremely difficult-to-treat cancer because of its rapidly progressive nature and high grade of resistance to all conventional, targeted and immunotherapies (Heinemann et al., 2014; Seicean, Petrusel, and Seicean, 2015). This is painfully evidenced by an unforgiving reality test when preclinical insights are tested in the clinic (Bates, 2017; Borazanci et al., 2017). Indeed, 47 clinical trials failed to show improvement over gemcitabine treatment, which is in sharp contrast with recent, encouraging discoveries in cancer immunotherapy in other tumour types (Bates, 2017). Even the highly promising immune checkpoint inhibitors programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have had no significant effect in PDAC (Jimenez-Luna et al., 2016; Mei, Du, and Ma, 2016).

The tumour microenvironment (TME) is believed to be a major confounding factor involved in the failure of all these new approaches (Haqq et al., 2014; Lunardi, Muschel, and Brunner, 2014; Tjomsland et al., 2011; Watt and Kocher, 2013; Wilson, Pirola, and Apte, 2014). A hallmark of this TME in PDAC is the strong desmoplastic reaction which results in a dense fibrotic/desmoplastic stroma that surrounds the pancreatic cancer cells (Heinemann et al., 2014; Watt and Kocher, 2013; Wilson et al., 2014). By acting as a mechanical and functional shield around the tumour, it is responsible for diminished delivery of anticancer agents because it causes a high intratumoural pressure and low microvascular density. The main orchestrator of this fierce stromal barrier is the pancreatic stellate cell (PSC). Once activated, these cells enhance the development, progression and invasion of PDAC through their extensive crosstalk with the tumour, resulting in reciprocal stimulation and therapy resistance (Feig et al., 2012; Heinemann et al., 2014; Watt and Kocher, 2013; Wilson et al., 2014).

Immune cells also comprise part of the TME. In this review we focus on natural killer (NK) cells. Although one of their primary functions is to kill cancer cells, less attention has been paid to these cytotoxic immune cells compared to T cells. NK cells are a subset of innate lymphoid cells (ILCs) and comprise about 5–15% of the circulating cell population (Chiossone, Vienne, Kerdiles, and Vivier, 2017; Fang, Xiao, and Tian, 2017). They were originally identified as an immune cell population with profound tumour cell killing abilities in vitro (Kiessling, Klein, Pross, and Wigzell, 1975; Kiessling, Klein, and Wigzell, 1975). However, numerous studies have since demonstrated their anticancer effect in different animal models as well as their benefit in human studies (Fang, Xiao, and Tian, 2017; Lopez-Soto, Gonzalez, Smyth, and Galluzzi, 2017; Pahl and Cerwenka, 2017). By using a well-defined set of activating and inhibitory receptors, NK cells are able to recognize and kill tumour cells while sparing healthy cells, more specifically because they sense a certain lack of major histocompatibility complex (MHC)-I molecules via their killer-cell immunoglobulin-like receptors (KIRs) (Chiossone et al., 2017). Moreover, once activated, NK cells can secrete a vast number of cytokines and chemokines such as interferon (IFN)γ, tumour necrosis factor (TNF)α, granulocyte-macrophage colony-stimulating factor (GM-CSF), chemokine (C-C motif) ligand (CCL) 1–5 and chemokine (C-X-C motif) ligand (CXCL) 8, which trigger activation and recruitment of other innate and adaptive immune cells that broaden and strengthen the anti-tumour immune response (Paul and Lal, 2017). These unique features make NK cells ideal targets for cancer immunotherapy as evidenced by an increasing number of both preclinical and clinical studies that show promising results in different tumour types (Chiossone et al., 2017; Fang, Xiao, and Tian, 2017).

However, the role of NK cells in PDAC has not been well defined, given only a few articles have focused specifically on NK cells. Nonetheless, data on their function and importance in PDAC are available in some studies. This systematic review summarises the current evidence on NK cells in PDAC and highlights several possible approaches that could be pursued in future PDAC research. To our knowledge, this is the first systematic review which focusses on the NK cells in pancreatic cancer.