Arch. Pharm. Res. DOI 10.1007/s12272-017-0951-9

Online ISSN 1976-3786 Print ISSN 0253-6269

REVIEW

Natural killer cells and tumor metastasis Hwan Hee Lee1,2 • Hyojeung Kang3 • Hyosun Cho1,2

Received: 5 June 2017 / Accepted: 21 August 2017 Ó The Pharmaceutical Society of Korea 2017

Abstract Natural killer (NK) cells are cytotoxic lymphocytes that recognize tumor cells or stressed cells through ‘missing-self’ signals, such as altered or absent expression of MHC class I molecules. The function of NK cells is regulated by the activation or inhibition of receptors present on their surface. The activation of NK cells results in cytotoxic activity on target cells through release of toxic granules and inflammatory cytokines. However, NK cells infiltrating tumors have been frequently shown to exhibit a skewed phenotype that includes decreased antitumor activity and enhanced protumor activities, such as angiogenesis and metastasis. In fact, many studies have reported that tumor microenvironments induce a protumor phenotype in NK cells. Here, we review the biological properties of NK cells in the context of tumorigenesis and tumor progression, with a specific focus on the interactions between NK cells and critical tumor microenvironments, such as epithelial-to-mesenchymal transition, matrix metalloproteinases, and tumor-associated chronic inflammation in tumor metastasis.

& Hyojeung Kang [email protected] & Hyosun Cho [email protected] 1

College of Pharmacy, Duksung Women’s University, Seoul 132-714, Republic of Korea

2

Innovative Drug Center, Duksung Women’s University, Seoul 132-714, Republic of Korea

3

College of Pharmacy, Research Institute of Pharmaceutical Sciences and Institute for Microorganisms, Kyungpook National University, Daegu 702-701, Republic of Korea

Keywords Natural killer cells
Tumor metastasis
EMT
MMPs
Chronic inflammation

Introduction Natural killer (NK) cells comprise 5–15% of the total lymphocyte population, which are the innate large granular lymphoid cells (Doherty and O’Farrelly 2000). In contrast to T cells, NK cells can lyse tumor cells without acquiring prior activation (Joyce and Pollard 2009). NK cells recognize tumors that avoid T cell-mediated killing, through abnormal or absent major histocompatibility antigen (MHC) I expression (Marincola et al. 2000). NK cells express a variety of molecules to kill target cells, which can be divided into two groups secretory and membrane-bound. The secretory molecules, such as perforin, granzyme (A and B), and granulysin are present inside granules and are released at the site of target cell contact (Vivier et al. 2008). Among these, granzyme B is known to enter the cytosol of target cells in a perforindependent manner and subsequently cleave Bid and procaspases. This sequence of events finally leads to apoptosis in the target cells (Vivier et al. 2008). The membranebound molecules comprise of activating (NKp46, NKp30, NKp44, NKG2D) and inhibiting (KIR, NKG2A) receptors that regulate NK-cell activity through the balance of signals that they transduce. The activating receptors bind to ligands on tumor cells or virus-infected cells, whereas the inhibitory receptors bind to MHC class I molecules (Colucci et al. 2003). These surface receptors are associated with additional functions of NK cells, which range from the production of cytokines and chemokines to immunomodulatory interactions with other immune cell

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types such as dendritic cells, macrophages, granulocytes, and T cells (Chiesa et al. 2005). Bidirectional communication between tumor cells and their microenviron-ment is important for the growth of tumor cells, which influences disease progress and patient prognosis. Malignant tumors have been often shown to escape from immune-mediated elimination. Moreover, there are reports that these tumors have modified certain immune cells to render them permissive to tumor progression. In fact, multiple factors have been implicated in limiting the anti-tumor effect of NK cells. These include the metastatic transition of tumor cells, the complex tumor structure, and the immunoregulatory tumor microenvironment. A number of soluble factors including immunosuppressive cytokines, metalloproteases as well as various tumor associated regulatory immune cells such as myeloid derived suppressor cells, and tumor associated fibroblasts have been shown to severely alter the expression and function of NK cell receptors, which results in an impairment of NK cell ability to recognize tumor cells, and could even promote tumor progression (Castriconi et al. 2003; Balsamo et al. 2009; Hoechst et al. 2009; Liu et al. 2009). Of note, several recent studies have reported that NK cells can also affect tumor cells in a variety of ways including the alteration of HLA-I, PD-L1, or NKG2D-L in tumor cells to gain epithelial-to-mesenchymal transition (EMT) phenotype for the prometastatic state(Chen et al. 2015; Dondero et al. 2016). In this review, we discuss the role of NK cells in tumor growth, progress, and metastasis, and examine the current data available suggesting possible roles for infiltrating NK cells in the evolution of tumor cells towards the metastatic stage. In addition, we summarize the recent studies that have investigated the interaction between NK cells and metastatic tumors in terms of epithelial-to-mesenchymal transition, matrix metalloproteases and chronic inflammation.

The functional receptors of NK cells NK cells are known to express CD56 in the absence of CD3, which can be identified by flow cytometry. NK (CD56?CD3-) cells also express CD16, the low-affinity Fc receptor (FccRIIIa or FccRIIIb), which mediates antibodydependent cell cytotoxicity by binding to the Fc portion of IgG (Cooper et al. 2001). These two major subsets of surface molecules, CD56 and CD16, are identified in human peripheral blood NK cells (Cooper et al. 2001). The subset of CD56 ? cells can be further divided into CD56dim and CD56bright depending on the intensity of detected CD56. The CD56dimCD16?subset has been found to constitute 90–95% of peripheral blood NK cells. This

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population contains high amounts of cytolytic granules (perforin, granzyme), which are cytotoxic to stressed cells and mediate antibody-dependent cell cytotoxicity (ADCC) (Cooper et al. 2001). The other NK cell subset consists of CD56brightCD16-/low cells that contribute to 5–10% of peripheral blood NK cell population. Even though the cytotoxicity of CD56brightCD16-/low cells is weak, they are able to secrete large amounts of cytokines such as IFNc and TNFa. This subset can undergo further maturation into CD56dimCD16? cells upon stimulation with specific cytokines such as IL-2, IL-12, and/or IL-15 (Ferlazzo et al. 2004; Romagnani et al. 2007). The effector function of NK cells is tightly regulated by activating and inhibitory receptors (Table 1). Human NK cells express eight distinct activating NK cell receptors, five immunoglobulin-like and three lectin-like molecules. Among the immunoglobulin-like receptors are NKp30, NKp44, and NKp46 also known as natural cytotoxicity receptors (NCR), and the three lectin-like receptors are NKG2D, NKG2C and NKG2E. NKG2D is a receptor for the stress-inducible MHC class I chain-related A and B (MICA/B), which are present on the surface of transformed host cells, and is also presented by cytotoxic T lymphocytes. NKG2C and NKG2E are receptors for the nonclassical MHC class I molecule HLA-E (Ryan et al. 1995; Braud et al. 1998; Bauer et al. 1999). The inhibitory receptors of human NK cells contain immunoglobulin superfamily (Ig-SF) killer cell inhibitory receptors (KIRs), immunoglobulin-like transcripts (ILT), and lectin-like receptors for NKG2A (or 2B). Intracellular signaling by either activating or inhibitory receptors is established upon their non-covalent association with intracytoplasmic tyrosine motifs as well as transmembrane adaptor proteins. The NCRs trigger their signaling pathway with immunoreceptor tyrosine-based inhibitory motifs (ITAM). Signaling from CD16 is also combined to the ITAM-bearing polypeptide CD3f and/or FcRc (Moretta et al. 2001). However, the lectin-like receptor, NKG2D, associates with the DAP10 adaptor protein, which does not contain the ITAM-bearing polypeptides (Wu et al. 1999; Chiesa et al. 2005). In contrast to NCRs, the inhibitory receptors are known to associate with immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that link them to the SH2 domain-containing protein tyrosine (SHP) phosphatases (Moretta et al. 1996; Lopez-Botet et al. 1997; Long 1999). The cytoplasmic signaling pathway of NK cells begins with the crosslinking of CD16, which then induces the activation of Syk (spleen tyrosine kinase) and ZAP70 (zeta-associated protein of 70 kDa) (Ting, et al. 1995). A number of other proteins such as 3BP2, Shc, Grb-2, phosphoinositide 3-kinase (PI3K), Vav-Rac1, Ras, MAPK (mitogen-activated protein kinase), and Erk (extracellular

Natural killer cells and tumor metastasis Table 1 Receptor expressed in human NK cells Receptors Activating receptors

Inhibiting receptors

Ligands

Functions

CD16

Fc (IgG)

ADCC receptor

NKp46

Viral HA, HSPG

Natural cytotoxicity receptors (NCR)

NKp44

Viral HA

NKp30

BAT-3, HSPG, B7-H6

KIR-S

HLA-C, B

CD94/NKG2C

HLA-E

Receptors for HLA class I or related molecules

CD94/NKG2E

HLA-E

NKG2D

ULBPs, MICA, MICB

CD160

HLA-C

CD244(2B4)

CD48

CD2 NTB-A

CD48, CD58 NTB-A

CD2 family

CS1

CS1

DNAM-1(CD226)

CD112, CD155

CD96

CD155

CD95

C8, C9

KIR-L

HLA-C, B and A

ILT

HLA class I

CD94/NKG2A

HLA-E

CD94/NKG2B

HLA-E

SIGLEC7, 9

Sialic acid

Receptors for nectins or nectin-like molecules

Self tolerance

BAT–3 HLA-B- associated transcript 3, HA hemagglutinin, HSPG heparan sulfate proteoglycans, ULBPs UL16 binding proteins, MIC MHC class I polypeptide-related sequence, NTB-A NK-T-B antigen, DNAM-1 DNAX accessory molecule, HLA human leukocyte antigen, KIR killer immunoglobulin-like receptor, ILT immunoglobulin-like transcripts

signal-regulated kinase) are also phosphorylated upon CD16 crosslinking with its target (Galandrini et al. 1997; Billadeau et al. 1998; Wei et al. 1998; Jevremovic et al. 2001). 3BP2, a cytoplasmic adaptor protein, is reported to be a positive regulator of NK cell mediated cytotoxicity, and is connected with phosphorylated PLCc and Vav proteins when NK cells are activated (Jevremovic et al. 2001). PI3 K is also a critical downstream factor of Syk in the cytolytic pathway, which results in sequential stimulation of the Rac–Mek–Erk pathway (Jiang et al. 2002). In addition, human NK cells present a group of co-stimulatory receptors, such as adhesion molecules (b1 and b2 integrins), members of the CD2 family (CD244, CD2, NTB-A, CS1, CRACC), DNAM-1, CD96, CD59, and NKp80. The signaling cascade from CD244 and NTB-A is not linked to DAP10 or ITAM-containing polypeptides. CD244 on human NK cells associates with SAP (SLAM-associated protein) which can bind to the Src-related PTK, FynT (Latour et al. 2003; Chen et al. 2004). It is still unclear whether CD244 serves an activating or inhibitory role.

Anti-tumor activity of NK cells Anti-tumor activity of NK cells was first described in 1975, which showed the capacity of NK cells to naturally lyse tumor cells (Waldhauer and Steinle 2008). Tumor-infiltrating NK cells have been reported to provide a strong anti-tumor activity with better disease prognosis in a variety of cancers. Impairment of NK-cell migration into colorectal carcinoma (CRC) tumor tissue was observed (Halama et al. 2011). Furthermore, intratumoral NK cells in non-small cell lung carcinoma (NSCLC) were found to be deeply defective in their capacity to activate degranulation and IFN-c production of NK cells (Platonova et al. 2011). Peng et al. showed that the function of NK cells is impaired by the tumor-associated monocytes/macrophages, whereby they negatively affect the expression of IFN-c, TNF-a and Ki-67, which are related to the anti-tumor activity of NK cells. In their subsequent study, the blockade of TGF-b was shown to restore the anti-tumor capability of NK cells by reducing the activity of tumorassociated monocytes/macrophages (Peng et al. 2017). Exhaustion of NK cells resulted in a decreased number of peripheral and intratumoral effector CD4?T-bet?cells

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(Th1), which produce IFN-c (Paul et al. 2016). The immune-gene signature data showed that the chemokine CXCL10, CCL5 and CCL2 driven tumor infiltration of NK cells resulted in enhanced cancer cell death. Moreover, the number of liver NK cells was considerably decreased during hepatocellular carcinoma (HCC) development (Chew et al. 2012). A 11-year cohort study on a Japanese population reported that high cytotoxic activity of peripheral-blood NK cells is associated with reduced cancer risk, while low cytotoxicity is associated with increased cancer risk (Imai et al. 2000). NK cells do not need to be selected for specific clones to achieve anti-tumor activity. Therefore, in hematopoietic stem cell transplantation, donorderived allo-reactive NK cells can provide effective antitumor activity without causing graft versus host disease (Moretta et al. 2011). Anti-tumor activity of NK cells can be demonstrated in several ways. The primary mechanism of anti-tumor activity is granule-mediated cytotoxicity. NK cells contain preformed perforin and granzyme, which are released upon receiving a signal for ADCC. ADCC has been suggested to mediate the antitumor effects of monoclonal antibody therapies that are widely applied in cancer therapy for solid tumors as well as hematologic malignancies (Kohrt et al. 2012). Another anti-tumor mechanism employed by NK cells is the production of cytokines such as TNF-a and IFN-c. TNF-a is a key inflammatory cytokine that causes tumorassociated capillary injury as well as induction of adaptive immune response (Balkwill 2009). IFN-c plays a critical role in protecting the host against microbial infection and tumor development (Moretta et al. 2001). NK cell-derived IFN-c can induce the polarization of Th1 cells, the inhibition of Foxp3?Tregs, and the development of tumor-directing cytotoxic CD8? T cells in the tumor microenvironment (Ikeda et al. 2002; Brillard et al. 2007). In this Th1-polarizing setting, various other immune-cells can also interact with NK cells to increase anti-tumor activity. Dendritic cells and macrophages participate in stimulating NK-cell activation, whereas neutrophils induce the terminal differentiation of NK cells (Bellora et al. 2010; Jaeger et al. 2012). Death receptor-induced apoptosis is an anti-tumor mechanism which involves lysis of target cells in a perforin-independent way. This cytotoxic pathway depends on the expression of two main TNF receptors, Fas (CD95) and TNF-related apoptosis-inducing ligand (TRAIL). TRAILmediated signaling stimulates spontaneous cytotoxicity against TRAIL-sensitive tumor cells (Zamai et al. 1998). All anti-tumor activities of NK cells are a result of a balance between signals from activating and inhibitory receptors.

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Tumor escape from NK-cell mediated cytotoxicity Immune surveillance is a process by which malignant cells (or transformed cells) are detected and destroyed by antitumor immune response systems. However, immunoediting often happens, wherein ‘‘edited’’ tumors can escape immune surveillance. The event of immunoediting results from not only the absence of anti-tumor immunity, but also the presence of active pro-tumor immunity, which stimulates tumor development. Tumor cells can evade anti-tumor activity of NK cells by modifying the expression of NK cell receptors (Table 2). The levels of NKG2D, NKp30, NKp46 and CD16, the primarily activating receptors on NK cells, were reported to be decreased in various cancer patients. NK cells from human breast cancer showed reduced expression of NKp30, NKG2D, DNAM-1, and CD16 as well as decreased NK cell function (Mamessier et al. 2011). In chronic lymphocytic leukemia (B-CLL), NK cell activity is attenuated by reduction of the expression of activating receptors such as NKG2D, DNAM-1, and NCRs (Parry et al. 2016). In addition, the frequency of NKG2D, NKp30, NKp46, and perforin positive NK cells was considerably down-regulated in patients with pancreatic cancer (PC), gastric cancer (GC), and colorectal cancer (CRC); this decrease is linked to disease progression (Peng et al. 2013). Low levels of NKp30, NKp46 and NKG2D expression along with reduced cytotoxic activity were observed on NK cells from cervical cancer patients (Garcia-Iglesias et al. 2009). NK cell dysfunction is also associated with increased expression of the inhibitory receptor NKG2A in human breast cancer, CRC and HCC (Mamessier et al. 2011; Bossard et al. 2012; Sun et al. 2017). There has also been a report of significantly high levels of KIR3DL1 ? NK cells in patients with PC, GC and CRC (Peng et al. 2013). Furthermore, tumors can modulate the expression of ligands for NK functional receptors which contributes to evasion of anti-tumor activity of NK cells. The shedding of soluble activating NKG2D ligands has been observed in breast cancer, CRC, and colon cancer, which leads to downregulation of NKG2D on NK cells (Bossard et al. 2012; de Kruijf et al. 2012). Similarly, the release of BAG6/BTA3, a soluble ligand for NKp30, decreased NK effector functions in chronic lymphocytic leukemia (Reiners et al. 2013). Interestingly, NK cell function can be modulated by other immune cells and specific cytokines from the tumor microenvironment. TGF-b, the representative immunosuppressive cytokine, has been shown to inhibit the expression of NKp30 and NKG2D on NK cells (Peng et al. 2013).

Natural killer cells and tumor metastasis Table 2 NK cell receptors in tumors Receptors

Ligand

Tumor

Expression

References

Activating CD16

Fc (IgG)

BC, MM, CRC

Decreased

Mamessier et al. (2011), Treon et al. (2005) and Rocca et al. (2016)

NKp46

Vimentin

PC, GC, CRC, AML, CC-2

Decreased

Peng et al. (2013), Garcia-Iglesias et al. (2009) and Sanchez-Correa et al. (2011)

BC, AML

Decreased

Amo et al. (2015) and Mercier-Bataille et al. (2014)

NKp30

B7-H6, BAG6

BC, HCC, PC, GC, CRC, CLL, AML, CC-2

Decreased

Mamessier et al. (2011), Peng et al. (2013), Garcia-Iglesias et al. (2009), Hoechst et al. (2009) and Sanchez-Correa et al. (2011)

CD94/ NKG2C

HLA-E

AML

Decreased

Sanchez-Correa et al. (2011)

NKG2D

MICs, ULBPs

BC, LC, CRC, CC-1, PC, GC, CC-2

Decreased

Mamessier et al. (2011), He et al. (2013), Peng, et al. (2013), GarciaIglesias et al. (2009) and de Kruijf et al. (2012)

NKp44

CD244(2B4)

CD48

AML

Decreased

Sanchez-Correa et al. (2011)

DNAM1(CD226)

CD155, CD112

BC, CC-1, AML

Decreased

Mamessier et al. (2011) and Sanchez-Correa et al. (2011)

KIR3DL1

HLA-A, -B, -C

PC, GC, CRC

Increased

Peng et al. (2013)

KIR2DL2/ L3

HLA-C

Melanoma

Increased

Vuletic´ et al. (2013)

NKG2A

HLA-E

BC, LC, CRC

Increased

Mamessier et al. (2011), Jin et al. (2014) and Bossard et al. (2012)

Inhibiting

BC breast cancer, MM multiple myeloma, PC pancreatic cancer, GC gastric cancer, CRC colorectal carcinoma, AML acute myeloid leukemia, CC-2 cervical cancer, PCNA proliferating cell nuclear antigen, HCC hepatocellular carcinoma, CLL chronic lymphocytic leukemia, LC lung cancer, CC-1 colon carcinoma

IL-4 can decrease the ability of NK cells to kill tumor cells (Marcenaro et al. 2005). Indole amine 2,3-dioxygenase (IDO) stimulates the production of the immunosuppressive Trp catabolite, L-kynurenine, which inhibits NKcell-mediated killing through downregulation of NKp46 and NKG2D expression in NK cells(Della Chiesa et al. 2006). The low levels of bridging integrator-1 (Bin1) and high levels of IDO in tumor draining lymph node (TDLN) correlated with a negative prognosis in esophageal squamous cell cancer (ESCC) (Jia et al. 2015). Many immune cells of the tumor microenvironment have also reported to directly suppress NK cell function. Tregs from patients with gastrointestinal sarcoma (GIST) were found to inhibit NK cell effector functions by weakening cytotoxicity and reducing IL-12-mediated IFN-c production (Ghiringhelli et al. 2006). Recently, myeloid derived suppressor cells (MDSCs) from patients with hepatocellular cancer (HCC) were suggested to inhibit NK cell function in a NKp30dependent way (Hoechst et al. 2009). Tumor-associated fibroblasts(TAF) from melanoma patients strongly inhibited NK-cell function by modulating NKp44, DNAM-1, and NKp30 on NK cells and this effect was directly associated with prostaglandin E2 (PGE2) released from TAFs. Similarly, TAFs from HCC and CRC also suppressed the anti-tumor activity of NK cells through PGE2 and IDO production (Li et al. 2012, 2013). Neuroblastoma

cells were shown to control the migration of NK cells by modulating the expression of CXCR4, CXCR3, and CX3CR1 on human NK cells (Castriconi et al. 2013). Additionally, tumor microenvironment factors like hypoxia induce NK cells to lose their ability to upregulate the expression of activating receptors such as NKp46, NKp30, NKp44, and NKG2D (Balsamo et al. 2013).

Tumor metastasis From a clinical point of view, the metastatic stage is the gravest stage of tumorigenesis, since metastasis results in more than 90% of cancer-related mortality. Today, we know that tumor metastasis needs a close cooperation between cancer cells and neighboring cells including immune cells, inflammatory cells, and stromal elements to make a favorable tumor environment. The course of tumor metastasis can be divided into four different steps. Initially, the motility of cancer cells is increased to invade epithelial linings/basal membranes and reach blood vessels or lymphatics. This is called epithelial-mesenchymal transition (EMT) (Kalluri and Weinberg 2009). Next, cancer cells intravasate into blood vessels; persistent inflammation could support this by secretion of soluble mediators that stimulate vascular permeability. In the third step, initial

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metastatic cells travel through the blood circulation. Finally, cell adhesion molecules such as integrins allow the extravasation of circulating cancer cells where they may interact with immune, inflammatory, and stromal cells to begin proliferating (Polyak and Weinberg 2009). Inflammatory cells play a critical role in tumor metastasis because they can degrade the extracellular matrix that goes through extensive proteolysis during cancer cell invasion. In this stage, several matrix metalloproteinases such as MMP2 and MMP9 are reported to support tumor invasiveness (Kitamura et al. 2007). In addition, proinflammatory cytokines (IL-1, TNF-a, and IL-6) are shown to promote tumor invasiveness as well as metastasis through the activation of NF-jB and STAT3 expression (Yu et al. 2007). The involvement of NK cells in tumor metastasis is illustrated in Fig. 1. NK cells and EMT The organization of tumor tissue is quite complex and is influenced by hypoxia, angiogenesis, and invasion. The forward-facing area of tumor tissue is known to obtain a prometastatic phenotype, which is a transitional phase during which epithelial-derived tumor cells switch their phenotype into a mesenchymal state. This epithelial-tomesenchymal transition (EMT) seems to be a ‘‘phenotype switching’’ process wherein tumors change from a

proliferative to a migratory and invasive state (Thiery et al. 2009). EMT was reported to have a critical role in tumor progress and metastasis. The induction of EMT was shown to be highly tissue-specific and is regulated by complex networks of tumor microenvironmental components including various immune cells. Immune cells may not only mount an antitumor immune response, but can also assist tumor progression, which often occurs in later stages of tumorigenesis (Hanahan and Coussens 2012). Recently, many studies have reported that EMT is positively associated with the presence of the suppressive state of immune cells including M2 macrophages, MDSC neutrophil granulocytes, and Tregs, which suggest an important role for different immune cell types in the induction of EMT. M2polarized tumor-associated macrophages (TAMs) stimulate EMT in pancreatic cancer cells through the TLR4/IL-10 signaling pathway (Liu et al. 2013). Myeloid-derived suppressor cells (MDSC) aggressively promote tumor cell dissemination by inducing EMT in murine melanoma (Marvel and Gabrilovich 2015). PMNs modify tumor cells to have a mesenchymal phenotype with low E-cadherin expression in human ovarian cancer (Mayer et al. 2016). The bidirectional interaction between EMT and NK cells has not been clearly understood yet. Lo´pez-Soto et al. observed the upregulation of NKG2D ligands (NKG2DLs) expression and down-regulation of MICA expression during EMT in colorectal tumor cells. Interestingly, the

Fig. 1 The involvement of NK cells in tumor metastasis. The NK cells are involved in EMT process, MMPs activation and chronic inflammation of tumor metastasis. The expressions of NKG2D, HLA-I, MICA/B and PD L1 (B7-H1) have been modulated during the EMT process of tumor cells to balance between anti-tumor activity of NK cells and NK immune-editing process. MMP-9, MMP 14 and MMP-25 were found to inhibit the activity of NK cells. In addition, IL-6 and IL-32 as cytokines, and NFkB and STAT3 as transcription factors were associated with the persistent inflammation of tumor metastasis

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expression of MICA/B was found to be increased in epithelial-characteristic tumor cells, whereas no expression of MICA/B was noticed in invasive and metastatic tumor cells. This suggests that the EMT process may improve the detection of tumor cells by NK cells in a NKG2D-dependent manner. However, the authors also speculated that metastatic tumor cells with no expression of MICA/B might undergo immune-editing process by the anti-tumor activity of NK cells (Lopez-Soto et al. 2013). TGF-b and EGF induced HLA-I downregulation was shown to be strongly associated with EMT in prostate tumor cells, which indicates that this phenomenon makes tumor cells resistant to the recognition by cytotoxic T cells, but enhance their susceptibility to NK-mediated anti-tumor responses (Chen et al. 2015). Another study showed that IFN-c released by NK cells induced a significant upregulation of PD-L1 (B7-H1) on metastatic tumor cells in human melanoma. This suggests that PD-L1/PD-1 pathway may contribute to an immune evasion mechanism employed by tumor cells in response to endogenous antitumor activity of NK cells (Taube et al. 2012). Chen et al. also observed a strong correlation between EMT progress and PD-L1 expression in data from human lung cancer patients (Chen, et al., 2014). Similarly, LAP/TGF-b and PD-L1 expression induced by mammarytumor-educated B cells suppress anti-tumor activity of NK cells (Zhang et al. 2016). Interestingly, Bellucci et al. reported that blocking JAK1 or JAK2 pathway increased susceptibility of various human tumor cells to NK cell mediated lysis (Bellucci et al. 2012). They also observed that incubation of tumor cells with IFNc induced the STAT1 signaling pathway and increased the expression of PD-L1. At the same time, this enhanced expression of PDL1 was blocked by shRNAs targeting JAK1, JAK2, or STAT1. Therefore, the authors suggest that JAK pathway inhibitors could be anti-tumor candidates by preventing IFN-induced inhibition of NK cell-mediated tumor cell lysis (Bellucci et al. 2015). In neuroblastomas, the expression of the poliovirus receptor (PVR), the ligand for activating receptors of NK cells, was found to be absent whereas the expression of B7H3, the ligand for inhibiting receptors of NK cells, was relatively high in metastatic tumor cells, which indicates that NK cells participate in modulating tumor cell phenotype (Bottino et al. 2014). Recently, Dondero et al. has reported that aggressive neuroblastomas do not persistently express PD-L1, but start expressing the ligand upon IFN-c stimulation (Dondero et al. 2016). NK cell maturation and differentiation has been shown to be regulated by the expression of the transcription factor Zeb2, which controls epithelial to mesenchymal transition in tumors, and a loss of Zeb2 expression results in impaired function of NK cells, which leads to tumor metastasis (Mary et al. 2015).

NK cells and matrix metalloproteinases Extracellular matrix (ECM) remodeling is a physiologically important process in cell migration and invasion. During cellular invasion, matrix metalloproteinases (MMPs) facilitate the degradation of ECM proteins for the subsequent remodeling stage. Multiple MMPs have been found to be expressed in NK cells of various species. To date, MMP-1, -2, -9, -14, -15, MT-2 and MT-6 MMP have been described in human NK cells (Vu and Werb 2000). MMPs are suggested to promote the extravasation of lymphocytes (NK cells and T cells) from blood vessels into the target sites. MMP-1 was reported to stimulate a human NK-cell invasion in response to CXCL12 (Goda et al. 2006). The number of invading NK-92 cells was decreased significantly in the presence of an MMP inhibitor, indicating that MMPs play a critical role in the migration of NK-92 cells (Edsparr et al. 2009). However, several studies have also reported that MMPs accelerate the progression of tumor metastasis by inhibiting the anti-tumor effects of NK cells. MMP-9 was shown to considerably suppress the cytotoxicity of NK cells in oral squamous cell carcinoma cells (Lee et al. 2008). Similarly, MMP-9 blocked the function of NK cells through inhibition of the expression of NKG2D, NKp30, and perforin as well as preventing the secretion of cytokines such as IFN-c and TNF-a (Peng et al. 2014). MT-6 MMP (MMP-25) was shown to reduce the function of human primary NK cells by serving as the proteinase responsible for CD16 down modulation on the surface of NK cells (Peruzzi et al. 2013). Blocking the activity of MMPs increased the expression of CD16 and enhanced ADCC activity of human primary NK cells during HIV infection (Liu et al. 2009). Furthermore, MMP inhibitors not only prohibited CD16 down modulation of NK cells but also enhanced CD16-mediated signaling in human NK cells (Zhou et al. 2013). MMP-9 and MMP-14 were reported to mediate MICA shedding of tumor cells which facilitates tumor evasion of NK cell–mediated immunity, which in turn can contribute to tumor metastasis (Liu et al. 2010; Sun et al. 2011). Microarray analysis on extranodal natural killer (NK)/T cell lymphoma specimens showed that the expression levels of MMP-2 and MMP-9 were closely linked to a poor prognosis, especially with invasive phenotype (Yu et al. 2013). Lin et al. found that HLA-G expression decreased NK cytotoxicity against mouse ovarian carcinoma, which positively correlated with the upregulation of MMP-15. Of note, treatment with siRNAs that block the expression of HLA-G and/or MMP-15 significantly inhibited tumor migration and metastasis (Lin et al. 2013). In a recent study, the expression of MMP-9 was found to be negatively correlated with the expression of NKG2D ligands in gastric cancer cells, and treatment with an MMP-

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9 inhibitor restored the downregulated expression of NKG2D ligands resulting in increased susceptibility of tumor cells to NK cells (Shiraishi et al. 2016). NK cells and chronic inflammation Inflammation is a part of the defensive immune responses of the body to fight and eliminate external or internal stimuli. When tissue homeostasis is disturbed, several innate immune cells including neutrophils, macrophages and NK cells immediately release cytokines, chemokines and ROS, which stimulate the mobilization and infiltration of leukocytes into the site of injury. Under normal conditions this inflammatory response is maintained for a short time; and can result in many pathological consequences such as cancer if it becomes chronic. Chronic inflammatory responses are in fact, known to play crucial roles at all stages of tumor progression including tumor initiation, promotion, invasion, and metastasis. The first observation of a strong association between inflammation and cancer was made by Rudolf Virchow and colleagues, when they reported the presence of infiltrating leukocytes within tumors (Balkwill and Mantovani 2001). Interestingly, an epidemiological study shows that more than 25% of all types of cancers are caused by chronic infection or chronic inflammation (Hussain and Harris 2007). Chronic bronchitis has been shown to be closely linked with high a incidence of lung cancer, and chronic pancreatitis is associated with an increased risk of pancreatic cancer. Also, the severity of Crohn’s disease and ulcerative colitis is correlated with an increase of colon adenocarcinoma (Schetter et al. 2010). The molecular mechanism that leads to cancer development in chronic inflammation is still under investigation, but several key inflammatory mediators including cytokines, chemokines, ROS, COX-2, NFjB and STAT3 are reported to contribute to tumor promotion. NK cells also participate in inflammation-mediated tumor invasion or metastasis through release of cytokines such as IL-6 or IL32, and signaling related to NFjB or STAT3 (VendraminiCosta and Carvalho 2012). IL-6 contributes to protumorigenic effect by the activation of the JAK/STAT3 and the RAS/ERK/C/EBP pathways, which signals for tumor growth, metastasis, and apoptosis blockage (Naugler and Karin 2008). Importantly, the upregulated expression of IL6 and STAT3 was observed in colon tumors derived from ulcerative colitis patients. Importantly, blocking IL-6 signaling was shown to be effective in chronic inflammationassociated cancer (Neurath and Finotto 2011). In fact, activation of STAT3 has been detected in a variety of cancers including breast, colon, gastric, lung, and prostate cancers (Grivennikov and Karin 2010). IL-32, a newly discovered cytokine that was originally called NK cell

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transcript 4, is mainly released by NK cells and has been shown to participate in chronic inflammation (Dahl et al. 1992). IL-32 is considerably increased in human cancers such as pancreatic cancer, colon cancer, lung cancer and cervical cancer (Hong et al. 2017). IL-32 was suggested to promote tumor invasion through the activation of NF-jB in lung adenocarcinoma (Tsai et al. 2014) and to stimulate tumor invasion and motility of osteosarcoma and breast cancer cells through the activation of AKT signaling (Wang et al. 2015; Zhou et al. 2015). However, several studies have reported that IL-32 actually prevents tumor development. Chen et al. showed that the inhibition of JAK2/STAT3 signaling by IL-32 reversed IL-6-induced EMT and tumor metastasis in pancreatic cancer cells (Chen et al. 2016). Overexpression of IL-32 blocked tumor cell growth and induced apoptosis through the inhibition of NFjB and Bcl-2 in hepatocellular carcinoma (Kang et al. 2012). Cheon et al. also reported that IL-32 increased the cytotoxic activity of NK cells through up-regulation of expression of Fas and UL16-binding protein 2 (ULBP2) in human chronic myeloid leukemia cells (Cheon et al. 2011).

Clinical applications of NK cells in cancer therapy Recent studies in NK cell immunotherapy have helped in advancement of cancer therapy. These advances include augmentation of antibody-dependent cytotoxicity (ADCC) of NK cells, modification of receptor-mediated activation, and adoptive immunotherapy with ex vivo-expanded, chimeric antigen receptor (CAR)-engineered, or immunoglobulin-modified NK cells. Several therapeutic antibodies targeting tumor-associated antigens work through activating NK cell-mediated ADCC. Romain et al. demonstrated that introduction of the Fc region of the IgG mAb to target antigens increased the activity of NK cell-mediated ADCC, which results in rapid target cell apoptosis (Romain et al. 2014). Another approach to enhance NK cell-mediated ADCC is combining agonistic antibodies targeting CD137, since the expression of CD137 is significantly upregulated during FcR-mediated ADCC. Agonistic antibodies targeting CD137 have been shown to enhance antitumor cytotoxicity of NK-cells including degranulation and secretion of IFN-c (Lin et al. 2008). Adoptive NK cell therapy was initiated with systemic administration of IL-2 to increase the antitumor activity of endogenous NK cells. However, cytokine stimulation promoted NK cell activation in vivo with limited success (Rosenberg et al. 1985). Recent approaches involve using anti-KIR Abs to block the inhibitory receptors of NK cells or using allogeneic NK cells to exploit their inherent alloreactivity (Karre 2002; Kohrt et al. 2014). Moreover,

Natural killer cells and tumor metastasis

ex vivo-expanded allogeneic NK cells have shown promise in immunotherapy in patients with poor-prognosis acute myeloid leukemia (Miller et al. 2005). Of note, ex vivoexpanded NK cells can be activated by cytokines such as IL-2, IL-12, IL-15, IL-18 and IL-21 during the expansion (Koepsell et al. 2013). In addition, treatment using fused NKG2D-IL-15 protein dramatically elevated the anti-tumor activity of NK cells in B16BL6 xenografted mice (Chen et al. 2017). A fused JAK inhibitor (JAKi)-IL-15 protein rescued the impairment of NK-cell-mediated anti-tumor immunity (Bottos et al. 2016). Recently, the function of NK cells in MHC class I-deficient tumors was recovered by treating NK cells with IL-21, which affects both the PI3KAKT-Foxol and STAT1 dependent pathways (Seo et al. 2017). Chimeric antigen receptors (CAR) have been applied widely to modulate the specificity of T cells against cancer. In the same way, engineered NK cells that express CARs against CD19, CD20, and HER2 have been successfully generated and CAR-transduced NK cells facilitate effective killing of tumor targets (Glienke et al. 2015). Interestingly, CAR-altered NK cells that target NKG2D ligands on cancer cells have also been introduced. This forces NK cells to be more cytotoxic against a variety of cancer (Chang et al. 2013). The use of bispecific (BiKE) or trispecific (TriKE) antibodies is a groundbreaking immunoglobulin-based strategy to redirect the cytotoxicity of NK cells to cancer. BiKE and TriKE are generated by combining single-chain Fv against CD16 with single-chain Fv against tumor-associated antigen, or two tumor-associated antigens, respectively. Bispecific CD16/CD19 BiKE and trispecific CD16/CD19/CD22 TriKE have been shown to efficiently activate NK cells through CD16 and increased cytolytic activity as well as cytokine production of NK cells (Gleason et al. 2014).

Conclusions In this review, we have addressed the different phenotypic characteristics of NK cells in anti-tumor as well as protumor microenvironments. NK cells inherently have a powerful anti-tumor activity. In the past decade, NK cells have been shown to prevent tumor growth, tumor invasion and tumor metastasis in diverse types of cancer. Of particular relevance are the reports of the positive correlation between the number of tumor-infiltrating NK cells or the immune-activating effect of NK cells and better disease prognosis in cancer patients. However, recent studies have demonstrated the role of dysfunctional NK cells in controlling tumor growth and metastasis, where the cytotoxic effect of NK cells on tumors seems to have been evaded by

a variety of factors in a tumor-promoting microenvironment. There have, in fact, been reports of tumor cells undergoing immunoediting, as well as of tumor-associated fibroblasts and tumor-induced abnormal immune cells showing tolerogenic or suppressive phenotypes. These cells were shown to inhibit either the activity of NK cells or the functional receptors that control the anti-tumor activity of NK cells. At the same time, NK cells can also directly contribute to the tumor-promoting microenvironment. For example, IFN-c, the main anti-tumor cytokine of NK cells, was reported to induce the adaptive immune evasion of tumor cells (Lv et al. 2015). Similarly, TNF-a was shown to be a potent inducer of EMT, which is a critical step in tumor metastasis (Lv et al. 2015). Here, we have discussed in detail, the association of NK cells with EMT, MMPs, and tumor-related persistent inflammation, which mounts an important challenge for the development of anti-cancer reagents, in that targeting one single aspect of cancer biology will not be efficient against severe metastatic cancers. A combination of anti-EMT reagents, inhibitors of MMPs, or anti-inflammatory drugs that target complex tumor microenvironments would prove more efficient in anti-cancer therapeutics. Additionally, a close relationship between NK cells and EMT, MMPs, and tumor-promoting inflammation provides critical immune check points that could be targets for immunotherapeutic anti-cancer reagents. Acknowledgements We gratefully acknowledge the financial support of the National Research Foundation of Korea (NRF) (2015R1C1A1A02037573). This research was also a part of a project titled ‘‘Development of Global Senior-friendly Health Functional Food Materials from Marine Resources‘‘, funded by the Ministry of Oceans and Fisheries, Korea. Compliance with ethical standards Conflict of interest The authors have no conflict of interest to declare.

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