Journal of Immunology Research

Journal of Immunology Research / 2018 / Article
Special Issue

Immunotherapy of Liver Diseases

View this Special Issue

Review Article | Open Access

Volume 2018 |Article ID 1206737 |

Pingyi Liu, Lingling Chen, Haiyan Zhang, "Natural Killer Cells in Liver Disease and Hepatocellular Carcinoma and the NK Cell-Based Immunotherapy", Journal of Immunology Research, vol. 2018, Article ID 1206737, 8 pages, 2018.

Natural Killer Cells in Liver Disease and Hepatocellular Carcinoma and the NK Cell-Based Immunotherapy

Academic Editor: Patrice Petit
Received19 Jun 2018
Accepted16 Aug 2018
Published04 Sep 2018


Nature killer (NK) cells play a critical role in host innate and adaptive immune defense against viral infections and tumors. NK cells are enriched in liver hematopoietic cells with unique NK repertories and functions to safeguard liver cells against hepatitis virus infection or malignancy transformation. However, accumulating evidences were found that the NK cells were modulated by liver diseases and liver cancers including hepatocellular carcinoma (HCC) and showed impaired functions failing to activate the elimination of the viral-infected cells or tumor cells and were further involved in the pathogenesis of liver injury and inflammation. The full characterization of circulation and intrahepatic NK cell phenotype and function in liver disease and liver cancer has not only provided new insight into the disease pathogenesis but has also discovered new targets for developing new NK cell-based therapeutic strategies. This review will discuss and summarize the NK cell phenotypic and functional changes in liver disease and HCC, and the NK cell-based immunotherapy approaches and progresses for cancers including HCC will also be reviewed.

1. Introduction

Liver is a vital organ in human; however, many people suffered from liver disease and liver cancers, such as hepatocellular carcinoma (HCC) which is one of the leading causes of cancer-related death worldwide [1]. The incidence of several major types of cancer, such as lung cancer, colon cancer, and prostate cancer, decreased in recent decade. In contrast, the incidence of HCC increased year by year [1]. In addition, the mortality rate of HCC is similar to the incidence rate which indicates that effective treatments for HCC are lacking in clinic [2, 3]. The major risk factors causing HCC include chronic viral infection, alcohol-related cirrhosis, and nonalcoholic steatohepatitis (NASH) [4]. Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections account for most of HCC cases worldwide [4, 5]; however, NASH will likely become a leading cause of HCC in the future, as the successful HBV vaccination and effective anti-HCV drugs will significantly reduce the number of chronic viral hepatitis patient in the near future [68].

In recent decades, accumulating evidences supported that the liver is also an immunological organ with predominant innate immunity [911]. The liver is enriched with innate immune cells including Kupffer cells, nature killer (NK) cells, NK T cells, and γδ T cells. These cells are critical in host defense against invading pathogens, liver injury and repair, and tumor development [11]. NK cells have been originally described as innate immune cells that are involved in the first line of immune defense against viral infections and tumors. In human, NK cells are phenotypically defined as CD3CD56+ large granular lymphocytes. Recently, a population of liver-resident NK cells was defined as CD49a+DX5 NK cells in mice. These cells originated from T hepatic hematopoietic progenitors and showed memory-like properties [12, 13]. The counterpart of these liver-resident NK cells was also characterized in human [14, 15]. The functions of NK cells are strictly regulated by the balance of activating receptors and inhibitory receptors interacting with target cells. These receptors can bind to specific ligands; for example, the major histocompatibility complex class (MHC-1) is expressed on healthy hepatocytes, which interacts with inhibitory receptors on NK cells and prevents the activation of NK cells. NK cells can directly eradicate infected cells or tumor cells lacking of MHC-1 molecule expression [16]. Once MHC-1 is downregulated by viral infection or tumorigenesis on the hepatocytes, the NK cells will loss the inhibitory signal controlled by the interaction of the NK inhibitory receptor with the MHC-1 complex, and the NK cells will be activated to kill infected hepatocytes. In the liver, the percentage of NK cells in total lymphocytes is around 5 times higher than the percentage in peripheral blood (PB) or spleen; thus, the NK cells were considered to play a very important role in the prevention of HCC and therefore were considered a potential cell therapy resource for the treatment of HCC [17].

In this review, we will summarize the phenotypes and functions of NK cells in chronic viral hepatitis, alcoholic liver disease, NASH, and HCC, and the progresses in NK cell-based immunotherapy for cancers but not limited to HCC are also reviewed.

2. NK Cells in Chronic Viral Hepatitis

Chronic viral hepatitis including HBV and HCV is the leading cause for the development of liver cirrhosis and subsequent HCC. HBV and HCV are pathogen replicate and grow inside of hepatocytes which alter the surface molecule for the interaction with NK cells. NK cells are critical in the early immune response for the clearance of virus. In chronic HBV and HCV patients, the percentage of circulating PB NK cells was lower than that in healthy controls [1821]. In addition, the production of proinflammatory cytokines such as interferon gamma (IFN-γ) and tumor necrosis factor-α (TNF-α) by NK cells was decreased in chronic HBV and HCV patients [18, 19, 22]. However, the impact of chronic viral infection on the cytolytic activity of NK cells was controversial. Several reports showed that NK cytolytic effector function was not changed [18, 20], while other researchers observed impaired NK cytolytic activity [2325]. The differences between these studies were probably due to the lack of standardized protocol and reagents as well as the heterogeneity of patients. The phenotype of NK cells between HBV and HCV patients was different, and NK cells showed an increase in the activating receptor NKG2D expression and a decrease in inhibitory receptor expression phenotype in chronic HCV patients, while in chronic HBV patients, the percentage of activating NKG2C+ NK cells increased and the inhibitory receptor expression was normal [18]. The reduced percentage and impaired function of NK cells in chronic viral hepatitis patients were believed to contribute to the disease progression and the transformation of HCC.

3. NK Cells in Alcoholic Liver Disease

Alcoholic liver disease is caused by alcohol abuse and also considered a major cause for cirrhosis and HCC, and around half of liver cirrhosis was related to alcohol [26]. NK cells were shown to play a critical role in resolving fibrosis by directly killing activated hepatic stellate cells (HSCs) and inducing HSC apoptosis by the production of IFN-γ [27]. However, chronic exposure to alcohol reduced the expression of NKG2D, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and IFN-γ on NK cells, which subsequently abrogated the antifibrotic effects of NK cells [28, 29]. In addition, the suppression of NK cell activation by chronic alcohol consumption was supported by several studies [3032]. The elevation of NKG2D, granzyme B, perforin, Fas ligand (FasL), TRAIL, and IFN-γ expression in NK cells by poly I:C stimulation was blocked in ethanol diet-fed mice [30]. More evidence and further study are needed to confirm whether the impairment of NK cell function by chronic alcohol consumption contributes to the development of alcohol-related HCC.

4. NK Cells in NASH

Although the incidence of chronic viral hepatitis decreases benefiting from the vaccinations and the advanced clinical therapies, the incidence of HCC gradually increases in developed countries. The nonalcoholic fatty liver disease (NAFLD) and NASH become two of the leading causes of HCC. However, there were only very limited studies about the role of NK cells in the pathogenesis of NAFLD and NASH. Less circulating PB NK cells and cytotoxic ability were found in patients with obesity than in healthy controls [33]. In contrast, another report showed that NK cell-derived mediators such as NKG2D and TRAIL mRNA levels were increased in NASH patients [34]. In a recent study, DX5+ NKp46+ NK cells were found to be increased in a NASH mouse model. Moreover, these NKp46+ NK cells regulate M1/M2 polarization of liver macrophages and inhibit the development of liver fibrosis in the NASH model [35]. So, how the dysregulation of NK cells in NASH contributes to HCC development is still largely unknown.

5. NK Cells and HCC

As we discussed above, NK cells are enriched in healthy liver, and they play critical roles in the surveillance of HCC. Similar to chronic viral hepatitis, the number of peripheral NK cells, especially CD56dimCD16+ NK cells, dramatically reduced in HCC patients [36, 37]. The NK cell number in the liver tumor area was also less than the NK cell number in the nontumor area and showed impaired cytotoxic ability as well as IFN-γ production [36, 38]. Moreover, the number of infiltrating and CD56+ NK cells positively correlated with HCC cancer cell apoptosis and patient survival [39, 40]. Several mechanisms had been proposed to explain the defect of the NK cell number and function in HCC; for example, infiltrated monocytes/macrophages in the peritumoral area induced rapid activation of NK cells. These activated NK cells then became exhausted and eventually died which was mediated by the CD48/2B4 interactions [38]. Myeloid-derived suppressor cells (MDSCs) may also interact with NK cells in HCC patients. MDSCs from HCC patients directly inhibited cytotoxicity and cytokine production of NK cells in a contact-dependent manner [41]. In addition, fibroblasts derived from HCC triggered NK cell dysfunction which was mediated by indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2) produced by the HCC cells, and these two natural immunosuppressants downregulate activating NK receptors [42]. Taken together, multiple mechanisms were involved in the NK cell malfunction, resulting in the development of HCC, and the lack of the NK cell number and the defects in function of NK cells facilitated the escape of tumor cells from immune surveillance.

6. NK Cell-Based Immunotherapy for Cancer

As we discussed above, NK cells, as a type of innate immune cell, are rapidly mobilized and serve as the first-line immune responders against viral-infected cells and tumor cells; however, the NK cells usually become inhibited in many cancers including HCC. Studies have been performed to explore NK cell-based immunotherapy for cancers. These approaches include either endogenous stimulation of the NK cells in patients, such as administration of cytokines to activate NK cells in cancer patients and treatment of the patients with antibodies that target the NK inhibitor receptor or checkpoint protein to activate NK cells or agonist of NK cell activating receptors, or adoptive NK cell transfer to the cancer patients. The therapeutic effects and progresses of these approaches will be reviewed in this article.

6.1. Cytokine Treatment to Increase the Cytotoxicity of NK Cells

Interleukin-2 (IL-2) was the first FDA-approved cytokine to boost cytotoxicity of NK cells [43]. However, IL-2 can act not only on NK cells but also on T cells including regulatory T cells (Tregs) which may inhibit NK cell function. Depletion of Tregs improved NK cell proliferation and outcome in acute myeloid leukemia (AML) therapy [44]. Several strategies were used to improve the efficiency of IL-2, including a modified IL-2 called “super-2” which can activate NK cells and cytotoxic CD8 T cells but not Tregs [45]. The fusion protein of IL-2 and NKG2D ligand only activated on NKG2D-expressing NK cells but on T cells [46].

Interleukin-15 (IL-15) is another cytokine to boost NK activity and increase cytotoxicity of both NK cells and CD8+ T cells without activating Tregs [47]. IL-15 treatment significantly increased the number of NK cells in both mouse model and human patients [48, 49]. Several IL-15 fusion proteins or modified IL-15 have been developed to increase their stability and efficiency [5052]. The clinical trials for the antitumor effect of IL-15, modified IL-15, and IL-15 fusion proteins are ongoing.

6.2. Antibodies to Modulate the NK Cytotoxic Function

Killer cell immunoglobulin-like receptors (KIRs) are expressed on NK cells and a minority of T cells [53]. KIRs bind with MHC-1 molecules to control the cytotoxic function of these immune cells. NK cells express both inhibitory KIR and activating KIR. The balance between the NK KIR inhibitory signal and KIR activating signal defines the NK effector function. Tumor cell-derived MHC-1 or class I-like molecules usually bind to KIR to inhibit NK cell activation [54]. Antibodies against inhibitory KIR showed promising effects on promoting NK cell cytotoxicity in mouse models [55]. However, the clinical trial did not show favorable effects of the KIR2D (an activating KIR receptor) antibody IPH2101 in multiple myeloma (MM) patients [56]. The lack of efficiency of the KIR2D antibody IPH2101 was probably due to the depletion of KIR2D-expressing NK cells by the antibody. The combination of lenalidomide, an immunomodulatory drug that can activate NK cells, with IPH2101 showed promising beneficial effects on MM patients in a phase I clinical trial [57].

Another NK receptor target to improve the cytotoxic function of NK cells is NKG2A. NKG2A is expressed in NK and CD8+ T cells as an inhibitor receptor. The heterodimer of NKG2A and CD94 can bind to HLA-E which is usually upregulated in tumor cells [54]; therefore, the tumor cells escaped the NK by this inhibitory signal. An antibody targeting NKG2A showed increased NK cell cytotoxicity and reduced disease progression in human primary leukemia or Epstein-Barr virus cell line-infused mouse model [58]. The clinical trial is ongoing to evaluate its safety and efficiency for cancer therapy.

Programmed cell death protein 1 (PD-1) is a well-known immune checkpoint of T cells. It is a cell surface receptor; the integration with its ligand on target cells suppresses the T cell activation and plays an important role in downregulating the immune system. Recently, the PD-1 receptor is found to be highly expressed on PB and tumor-infiltrating NK cells from patients with multiple myeloma (MM) and with digestive cancers including esophageal, colorectal, biliary, gastric, and liver cancers [59]. In the digestive cancer study, the investigators showed that PD-1 upregulation on NK cells correlated with poorer disease outcome in esophageal and liver cancers. In both the MM study and the digestive cancer study, PD-1-blocking antibody could increase the NK cytotoxic function in vitro targeting the tumor cell line or primary cancer cells. Moreover, the PD-1 antibodies inhibited the tumor growth in a xenograft mouse model [59]. These findings suggested that PD-1 blockade might be an efficient strategy in NK cell-based tumor immunotherapy.

In a recent study, Zhang et al. have found that the checkpoint inhibitory receptor TIGIT (“T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain”) was highly expressed on the exhausted tumor- (colorectal cancer) associated infiltrating NK cells. Monoclonal antibody-mediated blockade alone which targets TIGIT or in combination with the antibody against the PD-1 ligand PD-L1 increased the antitumor activity of both NK cells and T cells in preclinical mouse models and efficiently delays tumor growth [60]. Therapeutic strategies combining multiple blocking antibodies to treat cancer patients with NK cell exhaustion may improve the therapeutic efficacy, although the side effect of the antibody treatment needs to be carefully evaluated.

6.3. Agonist of NK Cell Activating Receptors

NK cells express a variety of activating receptors that play critical roles in regulating NK cell function. Major activating receptors on NK cells were well studied such as NKG2D, NKp30, NKp44, NKp46, and NKp80 [61]. Induction of NK cell activation to release cytokines or direct kill target cells requires combinatorial activating receptor synergy [62]. Activating receptor downregulation is observed in cancer patients and was correlated with poor disease outcomes [6366]. It is believed that the tumor cells express a high soluble amount of activation receptor ligand that induced the downregulation of activation receptors on NK cells in the patients [6668]. Modulating NK cell activating receptor expression by neutralizing their soluble ligand secreted by tumor cells in patients is a potential clinical therapeutic strategy.

6.4. Adoptive Transfer of NK Cells

NK cell adoptive transfer therapy requires the NK ex vivo expansion, in vivo long persistence, maximal in vivo activity, and NK cell killing specificity. The source of NK cells for adoptive transfer therapy can be autologous or allogeneic PB NK cells, stem cell-derived NK cells, and NK cell lines such as NK-92 and KHYG-1. Fresh or expanded NK cells derived from patients (autologous) failed to show improved clinical outcome in several types of cancers [69, 70]. The reason was that these transferred NK cells remained in circulation rather than in tumor tissue [69]. In contrast, NK cells derived from a healthy donor (allogeneic) showed a positive response in AML patients [71], and the following studies also showed encouraging results by using haploidentical NK cells for both elderly and pediatric AML patients [7274]. The clinical efficacy of the allogeneic NK cell adoptive immunotherapy to treat solid tumors has also been evaluated by several groups [7577]. Lin et al. had reported that percutaneous cryoablation combined with allogeneic NK adoptive transfer significantly increased the median progression-free survival of advanced HCC patients [75]. And multiple allogeneic NK cell infusion was associated with better prognosis in advanced cancers, including advanced HCC [75] and stage III pancreatic cancer [76]. Allogeneic NK cell immunotherapy for advanced non-small-cell lung cancer also showed a significant benefit in clinic [77]. The successful allogeneic NK cell adoptive transfer therapy may depend on the protocol for isolation and expansion and the purity of NK cells [7880].

To increase the killing specificity and efficiency of NK cell-based immunotherapy, several genetic modification approaches have been developed. The genetic modification for NK cells was not as easy as that for other immune cells such as T cells due to the resistance to retroviral infection. Several strategies were explored to improve the efficiency for transfection in NK cells [81, 82]. The introduction of CD16a, IL-15, and IL-2 in NK cells may increase the proliferation, activation, and cytotoxicity of NK cells [8385]. Recently, the successful application of the chimeric antigen receptor (CAR) in T cells was adopted in NK cells to increase the specificity and efficiency of NK cell immunotherapy. Compared with CAR-T cells, CAR-NK cells were short lived, which reduced the risk for autoimmunity and tumor transformation. The cytokines released from NK cells such as IFN-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF) were safer than the cytokine storm in CAR-T cell therapy [86]. As we mentioned above, due to the difficulties in expansion and transduction of primary NK cells, the only FDA-approved cell line for use in clinical trials, NK-92, was considered an ideal NK cell source for CAR-NK cell therapy [8789]. ErbB2/HER2-specific CAR-NK-92 cells showed very encouraging efficiency in target therapy of glioblastoma in an animal model [90]. CD19-specific CAR-NK-92 cells were sufficient to lyse CD19+ B-precursor leukemia cell lines as well as lymphoblasts from leukemia patients [91, 92]. In a preclinical study, CD5 CAR-NK-92 cells shows consistent, specific, and potent antitumor activity against T cell leukemia and lymphoma cell lines and primary tumor cells [93]. For the HCC, the first report was published very recently; glypican-3- (GPC3-) specific CAR-NK-92 cells showed potent antitumor activities in multiple HCC xenografts with both high and low GPC3 expressions. As expected, the GPC3 CAR-NK-92 cells did not show cytotoxicity to GFP3-negative HCC cells [94]. Currently, 9 clinical trials are ongoing to evaluate the safety and efficiency of CAR-NK cells, of which 7 trials are used for leukemia or lymphoma and 2 trials are for solid tumor. In the current preclinical study, some other NK sources are under investigation [95], such as the NK cells derived from hematopoietic progenitor cells [96] or from cord blood, and expanded in vitro with the aAPC K562-based system [97].

7. Summary

NK cells have been discovered for more than 40 years [98]; however, how to manipulate NK cells for the therapy of diseases remains elusive. The impairment of the function of NK cells was observed in many types of liver diseases including chronic viral hepatitis, alcoholic and nonalcoholic steatohepatitis, and HCC. Several approaches have been developed to boost the activity of NK cells for therapeutic purpose, but most of these studies are still in a preclinical stage. With the success of ex vivo genetic modification of T cells in the therapy of leukemia, it is promising that the similar strategy, as wells as other approaches to regulate the balance between activating and inhibitory receptors in NK cells, might also lead to the successful treatment for various liver diseases including HCC.


Pingyi Liu and Lingling Chen are the co-first authors.

Conflicts of Interest

The authors declare that they have no conflicts of interest.


  1. R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2017,” CA: A Cancer Journal for Clinicians, vol. 67, no. 1, pp. 7–30, 2017. View at: Publisher Site | Google Scholar
  2. J. Bruix, G. J. Gores, and V. Mazzaferro, “Hepatocellular carcinoma: clinical frontiers and perspectives,” Gut, vol. 63, no. 5, pp. 844–855, 2014. View at: Publisher Site | Google Scholar
  3. A. Forner, J. M. Llovet, and J. Bruix, “Hepatocellular carcinoma,” The Lancet, vol. 379, no. 9822, pp. 1245–1255, 2012. View at: Publisher Site | Google Scholar
  4. M. C. Wallace, D. Preen, G. P. Jeffrey, and L. A. Adams, “The evolving epidemiology of hepatocellular carcinoma: a global perspective,” Expert Review of Gastroenterology & Hepatology, vol. 9, no. 6, pp. 765–779, 2015. View at: Publisher Site | Google Scholar
  5. H. B. El-Serag, “Epidemiology of viral hepatitis and hepatocellular carcinoma,” Gastroenterology, vol. 142, no. 6, pp. 1264–1273.e1, 2012. View at: Publisher Site | Google Scholar
  6. S. Locarnini, A. Hatzakis, D. S. Chen, and A. Lok, “Strategies to control hepatitis B: public policy, epidemiology, vaccine and drugs,” Journal of Hepatology, vol. 62, no. 1, pp. S76–S86, 2015. View at: Publisher Site | Google Scholar
  7. N. Alkhouri, E. Lawitz, and F. Poordad, “Novel treatments for chronic hepatitis C: closing the remaining gaps,” Current Opinion in Pharmacology, vol. 37, pp. 107–111, 2017. View at: Publisher Site | Google Scholar
  8. C. Margini and J. F. Dufour, “The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment,” Liver International, vol. 36, no. 3, pp. 317–324, 2016. View at: Publisher Site | Google Scholar
  9. V. Racanelli and B. Rehermann, “The liver as an immunological organ,” Hepatology, vol. 43, Supplement 1, pp. S54–S62, 2006. View at: Publisher Site | Google Scholar
  10. C. N. Jenne and P. Kubes, “Immune surveillance by the liver,” Nature Immunology, vol. 14, no. 10, pp. 996–1006, 2013. View at: Publisher Site | Google Scholar
  11. B. Gao, W. I. Jeong, and Z. Tian, “Liver: an organ with predominant innate immunity,” Hepatology, vol. 47, no. 2, pp. 729–736, 2008. View at: Publisher Site | Google Scholar
  12. H. Peng, X. Jiang, Y. Chen et al., “Liver-resident NK cells confer adaptive immunity in skin-contact inflammation,” Journal of Clinical Investigation, vol. 123, no. 4, pp. 1444–1456, 2013. View at: Publisher Site | Google Scholar
  13. L. H. Zhang, J. H. Shin, M. D. Haggadone, and J. B. Sunwoo, “The aryl hydrocarbon receptor is required for the maintenance of liver-resident natural killer cells,” The Journal of Experimental Medicine, vol. 213, no. 11, pp. 2249–2257, 2016. View at: Publisher Site | Google Scholar
  14. L. Tang, H. Peng, J. Zhou et al., “Differential phenotypic and functional properties of liver-resident NK cells and mucosal ILC1s,” Journal of Autoimmunity, vol. 67, pp. 29–35, 2016. View at: Publisher Site | Google Scholar
  15. K. Hudspeth, M. Donadon, M. Cimino et al., “Human liver-resident CD56bright/CD16neg NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways,” Journal of Autoimmunity, vol. 66, pp. 40–50, 2016. View at: Publisher Site | Google Scholar
  16. M. G. Morvan and L. L. Lanier, “NK cells and cancer: you can teach innate cells new tricks,” Nature Reviews Cancer, vol. 16, no. 1, pp. 7–19, 2016. View at: Publisher Site | Google Scholar
  17. H. Sun, C. Sun, Z. Tian, and W. Xiao, “NK cells in immunotolerant organs,” Cellular & Molecular Immunology, vol. 10, no. 3, pp. 202–212, 2013. View at: Publisher Site | Google Scholar
  18. B. Oliviero, S. Varchetta, E. Paudice et al., “Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections,” Gastroenterology, vol. 137, no. 3, pp. 1151–1160.e7, 2009. View at: Publisher Site | Google Scholar
  19. O. Dessouki, Y. Kamiya, H. Nagahama et al., “Chronic hepatitis C viral infection reduces NK cell frequency and suppresses cytokine secretion: reversion by anti-viral treatment,” Biochemical and Biophysical Research Communications, vol. 393, no. 2, pp. 331–337, 2010. View at: Publisher Site | Google Scholar
  20. C. Morishima, D. M. Paschal, C. C. Wang et al., “Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing,” Hepatology, vol. 43, no. 3, pp. 573–580, 2006. View at: Publisher Site | Google Scholar
  21. P. Bonorino, M. Ramzan, X. Camous et al., “Fine characterization of intrahepatic NK cells expressing natural killer receptors in chronic hepatitis B and C,” Journal of Hepatology, vol. 51, no. 3, pp. 458–467, 2009. View at: Publisher Site | Google Scholar
  22. G. Ahlenstiel, R. H. Titerence, C. Koh et al., “Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa–dependent manner,” Gastroenterology, vol. 138, no. 1, pp. 325–335.e2, 2010. View at: Publisher Site | Google Scholar
  23. J. Corado, F. Toro, H. Rivera, N. E. Bianco, L. Deibis, and J. B. De Sanctis, “Impairment of natural killer (NK) cytotoxic activity in hepatitis C virus (HCV) infection,” Clinical and Experimental Immunology, vol. 109, no. 3, pp. 451–457, 1997. View at: Publisher Site | Google Scholar
  24. G. Pár, D. Rukavina, E. R. Podack et al., “Decrease in CD3-negative-CD8dim+ and Vδ2/Vγ9 TcR+ peripheral blood lymphocyte counts, low perforin expression and the impairment of natural killer cell activity is associated with chronic hepatitis C virus infection,” Journal of Hepatology, vol. 37, no. 4, pp. 514–522, 2002. View at: Publisher Site | Google Scholar
  25. J. Nattermann, G. Feldmann, G. Ahlenstiel, B. Langhans, T. Sauerbruch, and U. Spengler, “Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C,” Gut, vol. 55, no. 6, pp. 869–877, 2006. View at: Publisher Site | Google Scholar
  26. B. Gao and R. Bataller, “Alcoholic liver disease: pathogenesis and new therapeutic targets,” Gastroenterology, vol. 141, no. 5, pp. 1572–1585, 2011. View at: Publisher Site | Google Scholar
  27. S. Radaeva, R. Sun, B. Jaruga, V. T. Nguyen, Z. Tian, and B. Gao, “Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor–related apoptosis-inducing ligand–dependent manners,” Gastroenterology, vol. 130, no. 2, pp. 435–452, 2006. View at: Publisher Site | Google Scholar
  28. W. I. Jeong, O. Park, and B. Gao, “Abrogation of the antifibrotic effects of natural killer cells/interferon-γ contributes to alcohol acceleration of liver fibrosis,” Gastroenterology, vol. 134, no. 1, pp. 248–258, 2008. View at: Publisher Site | Google Scholar
  29. H. S. Yi, Y. S. Lee, J. S. Byun et al., “Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice,” Hepatology, vol. 60, no. 3, pp. 1044–1053, 2014. View at: Publisher Site | Google Scholar
  30. H. N. Pan, R. Sun, B. Jaruga, F. Hong, W. H. Kim, and B. Gao, “Chronic ethanol consumption inhibits hepatic natural killer cell activity and accelerates murine cytomegalovirus-induced hepatitis,” Alcoholism: Clinical and Experimental Research, vol. 30, no. 9, pp. 1615–1623, 2006. View at: Publisher Site | Google Scholar
  31. S. Støy, A. Dige, T. D. Sandahl et al., “Cytotoxic T lymphocytes and natural killer cells display impaired cytotoxic functions and reduced activation in patients with alcoholic hepatitis,” American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 308, no. 4, pp. G269–G276, 2015. View at: Publisher Site | Google Scholar
  32. K. Cui, G. Yan, X. Zheng et al., “Suppression of natural killer cell activity by regulatory NKT10 cells aggravates alcoholic hepatosteatosis,” Frontiers in Immunology, vol. 8, article 1414, 2017. View at: Publisher Site | Google Scholar
  33. D. O'Shea, T. J. Cawood, C. O'Farrelly, and L. Lynch, “Natural killer cells in obesity: impaired function and increased susceptibility to the effects of cigarette smoke,” PLoS One, vol. 5, no. 1, article e8660, 2010. View at: Publisher Site | Google Scholar
  34. A. Kahraman, M. Schlattjan, P. Kocabayoglu et al., “Major histocompatibility complex class I–related chains A and B (MIC A/B): a novel role in nonalcoholic steatohepatitis,” Hepatology, vol. 51, no. 1, pp. 92–102, 2010. View at: Publisher Site | Google Scholar
  35. A. C. Tosello-Trampont, P. Krueger, S. Narayanan, S. G. Landes, N. Leitinger, and Y. S. Hahn, “NKp46+ natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice,” Hepatology, vol. 63, no. 3, pp. 799–812, 2016. View at: Publisher Site | Google Scholar
  36. L. Cai, Z. Zhang, L. Zhou et al., “Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients,” Clinical Immunology, vol. 129, no. 3, pp. 428–437, 2008. View at: Publisher Site | Google Scholar
  37. A. Fathy, M. M. Eldin, L. Metwally, M. Eida, and M. Abdel-Rehim, “Diminished absolute counts of CD56dim and CD56bright natural killer cells in peripheral blood from Egyptian patients with hepatocellular carcinoma,” The Egyptian Journal of Immunology, vol. 16, no. 2, pp. 17–25, 2009. View at: Google Scholar
  38. Y. Wu, D. M. Kuang, W. D. Pan et al., “Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions,” Hepatology, vol. 57, no. 3, pp. 1107–1116, 2013. View at: Publisher Site | Google Scholar
  39. V. Chew, J. Chen, D. Lee et al., “Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma,” Gut, vol. 61, no. 3, pp. 427–438, 2012. View at: Publisher Site | Google Scholar
  40. V. Chew, C. Tow, M. Teo et al., “Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients,” Journal of Hepatology, vol. 52, no. 3, pp. 370–379, 2010. View at: Publisher Site | Google Scholar
  41. B. Hoechst, T. Voigtlaender, L. Ormandy et al., “Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor,” Hepatology, vol. 50, no. 3, pp. 799–807, 2009. View at: Publisher Site | Google Scholar
  42. T. Li, Y. Yang, X. Hua et al., “Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO,” Cancer Letters, vol. 318, no. 2, pp. 154–161, 2012. View at: Publisher Site | Google Scholar
  43. L. J. Burns, D. J. Weisdorf, T. E. DeFor et al., “IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: a phase I/II trial,” Bone Marrow Transplantation, vol. 32, no. 2, pp. 177–186, 2003. View at: Publisher Site | Google Scholar
  44. V. Bachanova, S. Cooley, T. E. Defor et al., “Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein,” Blood, vol. 123, no. 25, pp. 3855–3863, 2014. View at: Publisher Site | Google Scholar
  45. A. M. Levin, D. L. Bates, A. M. Ring et al., “Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’,” Nature, vol. 484, no. 7395, pp. 529–533, 2012. View at: Publisher Site | Google Scholar
  46. R. Ghasemi, E. Lazear, X. Wang et al., “Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy,” Nature Communications, vol. 7, article 12878, 2016. View at: Publisher Site | Google Scholar
  47. A. H. Pillet, J. Thèze, and T. Rose, “Interleukin (IL)-2 and IL-15 have different effects on human natural killer lymphocytes,” Human Immunology, vol. 72, no. 11, pp. 1013–1017, 2011. View at: Publisher Site | Google Scholar
  48. K. C. Conlon, E. Lugli, H. C. Welles et al., “Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer,” Journal of Clinical Oncology, vol. 33, no. 1, pp. 74–82, 2015. View at: Publisher Site | Google Scholar
  49. M. A. Cooper, J. E. Bush, T. A. Fehniger et al., “In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells,” Blood, vol. 100, no. 10, pp. 3633–3638, 2002. View at: Publisher Site | Google Scholar
  50. M. Thaysen-Andersen, E. Chertova, C. Bergamaschi et al., “Recombinant human heterodimeric IL-15 complex displays extensive and reproducible N- and O-linked glycosylation,” Glycoconjugate Journal, vol. 33, no. 3, pp. 417–433, 2016. View at: Publisher Site | Google Scholar
  51. Y. Chen, B. Chen, T. Yang et al., “Human fused NKG2D–IL-15 protein controls xenografted human gastric cancer through the recruitment and activation of NK cells,” Cellular & Molecular Immunology, vol. 14, no. 3, pp. 293–307, 2017. View at: Publisher Site | Google Scholar
  52. M. Rosario, B. Liu, L. Kong et al., “The IL-15-based ALT-803 complex enhances FcγRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas,” Clinical Cancer Research, vol. 22, no. 3, pp. 596–608, 2016. View at: Publisher Site | Google Scholar
  53. E. Alari-Pahissa, C. Grandclement, B. Jeevan-Raj, and W. Held, “Inhibitory receptor-mediated regulation of natural killer cells,” Critical Reviews in Immunology, vol. 34, no. 6, pp. 455–465, 2014. View at: Publisher Site | Google Scholar
  54. L. Martinet and M. J. Smyth, “Balancing natural killer cell activation through paired receptors,” Nature Reviews Immunology, vol. 15, no. 4, pp. 243–254, 2015. View at: Publisher Site | Google Scholar
  55. F. Romagne, P. Andre, P. Spee et al., “Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells,” Blood, vol. 114, no. 13, pp. 2667–2677, 2009. View at: Publisher Site | Google Scholar
  56. N. Korde, M. Carlsten, M. J. Lee et al., “A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma,” Haematologica, vol. 99, no. 6, pp. e81–e83, 2014. View at: Publisher Site | Google Scholar
  57. D. M. Benson Jr, A. D. Cohen, S. Jagannath et al., “A phase I trial of the anti-KIR antibody IPH2101 and lenalidomide in patients with relapsed/refractory multiple myeloma,” Clinical Cancer Research, vol. 21, no. 18, pp. 4055–4061, 2015. View at: Publisher Site | Google Scholar
  58. L. Ruggeri, E. Urbani, P. Andre et al., “Effects of anti-NKG2A antibody administration on leukemia and normal hematopoietic cells,” Haematologica, vol. 101, no. 5, pp. 626–633, 2016. View at: Publisher Site | Google Scholar
  59. Y. Liu, Y. Cheng, Y. Xu et al., “Increased expression of programmed cell death protein 1 on NK cells inhibits NK-cell-mediated anti-tumor function and indicates poor prognosis in digestive cancers,” Oncogene, vol. 36, no. 44, pp. 6143–6153, 2017. View at: Publisher Site | Google Scholar
  60. Q. Zhang, J. Bi, X. Zheng et al., “Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity,” Nature Immunology, vol. 19, no. 7, pp. 723–732, 2018. View at: Publisher Site | Google Scholar
  61. R. W. Johnstone, A. J. Frew, and M. J. Smyth, “The TRAIL apoptotic pathway in cancer onset, progression and therapy,” Nature Reviews Cancer, vol. 8, no. 10, pp. 782–798, 2008. View at: Publisher Site | Google Scholar
  62. E. O. Long, H. Sik Kim, D. Liu, M. E. Peterson, and S. Rajagopalan, “Controlling natural killer cell responses: integration of signals for activation and inhibition,” Annual Review of Immunology, vol. 31, no. 1, pp. 227–258, 2013. View at: Publisher Site | Google Scholar
  63. T. Garcia-Iglesias, A. del Toro-Arreola, B. Albarran-Somoza et al., “Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions,” BMC Cancer, vol. 9, no. 1, p. 186, 2009. View at: Publisher Site | Google Scholar
  64. C. Kellner, T. Maurer, D. Hallack et al., “Mimicking an induced self phenotype by coating lymphomas with the NKp30 ligand B7-H6 promotes NK cell cytotoxicity,” The Journal of Immunology, vol. 189, no. 10, pp. 5037–5046, 2012. View at: Publisher Site | Google Scholar
  65. N. F. Delahaye, S. Rusakiewicz, I. Martins et al., “Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors,” Nature Medicine, vol. 17, no. 6, pp. 700–707, 2011. View at: Publisher Site | Google Scholar
  66. M. Semeraro, S. Rusakiewicz, V. Minard-Colin et al., “Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients,” Science Translational Medicine, vol. 7, no. 283, article 283ra55, 2015. View at: Publisher Site | Google Scholar
  67. V. Groh, J. Wu, C. Yee, and T. Spies, “Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation,” Nature, vol. 419, no. 6908, pp. 734–738, 2002. View at: Publisher Site | Google Scholar
  68. B. K. Kaiser, D. Yim, I. T. Chow et al., “Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands,” Nature, vol. 447, no. 7143, pp. 482–486, 2007. View at: Publisher Site | Google Scholar
  69. M. R. Parkhurst, J. P. Riley, M. E. Dudley, and S. A. Rosenberg, “Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression,” Clinical Cancer Research, vol. 17, no. 19, pp. 6287–6297, 2011. View at: Publisher Site | Google Scholar
  70. N. Sakamoto, T. Ishikawa, S. Kokura et al., “Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer,” Journal of Translational Medicine, vol. 13, no. 1, p. 277, 2015. View at: Publisher Site | Google Scholar
  71. L. Ruggeri, M. Capanni, E. Urbani et al., “Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants,” Science, vol. 295, no. 5562, pp. 2097–2100, 2002. View at: Publisher Site | Google Scholar
  72. A. Curti, L. Ruggeri, A. D'Addio et al., “Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients,” Blood, vol. 118, no. 12, pp. 3273–3279, 2011. View at: Publisher Site | Google Scholar
  73. J. S. Miller, Y. Soignier, A. Panoskaltsis-Mortari et al., “Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer,” Blood, vol. 105, no. 8, pp. 3051–3057, 2005. View at: Publisher Site | Google Scholar
  74. J. E. Rubnitz, H. Inaba, R. C. Ribeiro et al., “NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia,” Journal of Clinical Oncology, vol. 28, no. 6, pp. 955–959, 2010. View at: Publisher Site | Google Scholar
  75. M. Lin, S. Liang, X. Wang et al., “Cryoablation combined with allogenic natural killer cell immunotherapy improves the curative effect in patients with advanced hepatocellular cancer,” Oncotarget, vol. 8, no. 47, pp. 81967–81977, 2017. View at: Publisher Site | Google Scholar
  76. M. Lin, M. Alnaggar, S. Liang et al., “An important discovery on combination of irreversible electroporation and allogeneic natural killer cell immunotherapy for unresectable pancreatic cancer,” Oncotarget, vol. 8, no. 60, pp. 101795–101807, 2017. View at: Publisher Site | Google Scholar
  77. M. Lin, S. Z. Liang, X. H. Wang et al., “Clinical efficacy of percutaneous cryoablation combined with allogenic NK cell immunotherapy for advanced non-small cell lung cancer,” Immunologic Research, vol. 65, no. 4, pp. 880–887, 2017. View at: Publisher Site | Google Scholar
  78. A. Bishara, D. de Santis, C. C. Witt et al., “The beneficial role of inhibitory KIR genes of HLA class I NK epitopes in haploidentically mismatched stem cell allografts may be masked by residual donor-alloreactive T cells causing GVHD,” Tissue Antigens, vol. 63, no. 3, pp. 204–211, 2004. View at: Publisher Site | Google Scholar
  79. S. M. Davies, L. Ruggieri, T. DeFor et al., “Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Killer immunoglobulin-like receptor,” Blood, vol. 100, no. 10, pp. 3825–3827, 2002. View at: Publisher Site | Google Scholar
  80. D. A. Knorr, V. Bachanova, M. R. Verneris, and J. S. Miller, “Clinical utility of natural killer cells in cancer therapy and transplantation,” Seminars in Immunology, vol. 26, no. 2, pp. 161–172, 2014. View at: Publisher Site | Google Scholar
  81. T. Sutlu, S. Nystrom, M. Gilljam, B. Stellan, S. E. Applequist, and E. Alici, “Inhibition of intracellular antiviral defense mechanisms augments lentiviral transduction of human natural killer cells: implications for gene therapy,” Human Gene Therapy, vol. 23, no. 10, pp. 1090–1100, 2012. View at: Publisher Site | Google Scholar
  82. V. F. van Tendeloo, P. Ponsaerts, F. Lardon et al., “Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells,” Blood, vol. 98, no. 1, pp. 49–56, 2001. View at: Publisher Site | Google Scholar
  83. B. Clémenceau, R. Vivien, C. Pellat, M. Foss, G. Thibault, and H. Vié, “The human natural killer cytotoxic cell line NK-92, once armed with a murine CD16 receptor, represents a convenient cellular tool for the screening of mouse mAbs according to their ADCC potential,” MAbs, vol. 5, no. 4, pp. 587–594, 2013. View at: Publisher Site | Google Scholar
  84. C. Sahm, K. Schonfeld, and W. S. Wels, “Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor,” Cancer Immunology, Immunotherapy, vol. 61, no. 9, pp. 1451–1461, 2012. View at: Publisher Site | Google Scholar
  85. S. Nagashima, R. Mailliard, Y. Kashii et al., “Stable transduction of the interleukin-2 gene into human natural killer cell lines and their phenotypic and functional characterization in vitro and in vivo,” Blood, vol. 91, no. 10, pp. 3850–3861, 1998. View at: Google Scholar
  86. H. Klingemann, “Are natural killer cells superior CAR drivers?” Oncoimmunology, vol. 3, no. 4, article e28147, 2014. View at: Publisher Site | Google Scholar
  87. G. Suck, M. Odendahl, P. Nowakowska et al., “NK-92: an ‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy,” Cancer Immunology, Immunotherapy, vol. 65, no. 4, pp. 485–492, 2016. View at: Publisher Site | Google Scholar
  88. C. Zhang, P. Oberoi, S. Oelsner et al., “Chimeric antigen receptor-engineered NK-92 cells: an off-the-shelf cellular therapeutic for targeted elimination of cancer cells and induction of protective antitumor immunity,” Frontiers in Immunology, vol. 8, p. 533, 2017. View at: Publisher Site | Google Scholar
  89. P. Nowakowska, A. Romanski, N. Miller et al., “Clinical grade manufacturing of genetically modified, CAR-expressing NK-92 cells for the treatment of ErbB2-positive malignancies,” Cancer Immunology, Immunotherapy, vol. 67, no. 1, pp. 25–38, 2018. View at: Publisher Site | Google Scholar
  90. C. Zhang, M. C. Burger, L. Jennewein et al., “ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma,” Journal of the National Cancer Institute, vol. 108, no. 5, 2016. View at: Publisher Site | Google Scholar
  91. A. Romanski, C. Uherek, G. Bug et al., “CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies,” Journal of Cellular and Molecular Medicine, vol. 20, no. 7, pp. 1287–1294, 2016. View at: Publisher Site | Google Scholar
  92. S. Oelsner, M. E. Friede, C. Zhang et al., “Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma,” Cytotherapy, vol. 19, no. 2, pp. 235–249, 2017. View at: Publisher Site | Google Scholar
  93. K. H. Chen, M. Wada, K. G. Pinz et al., “Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor,” Leukemia, vol. 31, no. 10, pp. 2151–2160, 2017. View at: Publisher Site | Google Scholar
  94. M. Yu, H. Luo, M. Fan et al., “Development of GPC3-specific chimeric antigen receptor-engineered natural killer cells for the treatment of hepatocellular carcinoma,” Molecular Therapy, vol. 26, no. 2, pp. 366–378, 2018. View at: Publisher Site | Google Scholar
  95. K. Rezvani, R. Rouce, E. Liu, and E. Shpall, “Engineering natural killer cells for cancer immunotherapy,” Molecular Therapy, vol. 25, no. 8, pp. 1769–1781, 2017. View at: Publisher Site | Google Scholar
  96. E. Lowe, L. C. Truscott, and S. N. De Oliveira, “In vitro generation of human NK cells expressing chimeric antigen receptor through differentiation of gene-modified hematopoietic stem cells,” Methods in Molecular Biology, vol. 1441, pp. 241–251, 2016. View at: Publisher Site | Google Scholar
  97. E. Liu, Y. Tong, G. Dotti et al., “Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity,” Leukemia, vol. 32, no. 2, pp. 520–531, 2018. View at: Publisher Site | Google Scholar
  98. R. B. Herberman, M. E. Nunn, H. T. Holden, and D. H. Lavrin, “Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells,” International Journal of Cancer, vol. 16, no. 2, pp. 230–239, 1975. View at: Publisher Site | Google Scholar

Copyright © 2018 Pingyi Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.