Muhammad Sajid
Lianxin Liu1*
Cheng Sun- 1Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, China
- 2Transplant and Immunology Laboratory, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- 3Chinese Academy of Sciences (CAS) Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- 4Institute of Immunology, University of Science and Technology of China, Hefei, China
Hepatocellular carcinoma (HCC) remains an important complication of chronic liver disease, especially when cirrhosis occurs. Existing treatment strategies include surgery, loco-regional techniques, and chemotherapy. Natural killer cells are distinctive cytotoxic lymphocytes that play a vital role in fighting tumors and infections. As an important constituent of the innate immune system against cancer, phenotypic and functional deviations of NK cells have been demonstrated in HCC patients who also exhibit perturbation of the NK-activating receptor/ligand axis. The rate of recurrence of tumor-infiltrating and circulating NK cells are positively associated with survival benefits in HCC and have prognostic significance, suggesting that NK cell dysfunction is closely related to HCC progression. NK cells are the first-line effector cells of viral hepatitis and play a significant role by directly clearing virus-infected cells or by activating antigen-specific T cells by producing IFN-γ. In addition, chimeric antigen receptor (CAR) engineered NK cells suggest an exclusive opportunity to produce CAR-NKs with several specificities with fewer side effects. In the present review, we comprehensively discuss the innate immune landscape of the liver, particularly NK cells, and the impact of tumor immune microenvironment (TIME) on the function of NK cells and the biological function of HCC. Furthermore, the role of NK cells in HCC and HBV-induced HCC has also been comprehensively elaborated. We also elaborate on available NK cell-based immunotherapeutic approaches in HCC treatment and summarize current advancements in the treatment of HCC. This review will facilitate researchers to understand the importance of the innate immune landscape of NK cells and lead to devising innovative immunotherapeutic strategies for the systematic treatment of HCC.
Introduction
Primary liver cancer is the fifth most common cancer with high incidence and prevalence throughout the world. Epidemiological data revealed that liver cancer is considered the second-highest mortality rate among different types of cancer, accounting for about 9.1% of total cancer deaths (1, 2). The most common liver cancer is hepatocellular carcinoma which accounts for approximately 90% of cancers worldwide and 75% occurring in Asia and it is the 4th leading cause of mortality (3, 4). Several factors are involved in the development of liver cancers, the most important include genetic and environmental factors. Genetic factors include various single nucleotide polymorphisms (SNPs) and some rare monogenic diseases that influence the individual to HCC (5, 6). The most dominant environmental risk factors include chronic infection with hepatitis B or C virus, alcoholic abuse, nonalcoholic fatty liver disease (NAFLD), the metabolic disorders associated with diabetes mellitus, and obesity that portend a huge trajectory in the frequency of HCC progression (7). Due to the widespread metabolic disorders, liver cancer is supposed to be a rapidly growing cause of cancer-associated mortality. A model-based simulation predicts the increase in HCC mortality globally until 2030. The high frequency of HCC incidence emphasizes the tremendous significance of liver cancers (8).
The liver is a vital organ and is involved in an array of the different physiological functions of the body which include glucose storage, metabolism, detoxification, vitamin storage, cholesterol, and lipid homeostasis, blood and immune regulation, and xenobiotics processing (9). The liver is constantly assaulted by different pathogens and must proficiently respond to maintain host survival and integrity. Intricate cellular surveillance approaches have been developed that facilitate the individual cells to distinguish damage and pathogen-associated molecular patterns. The capability of the liver to cope with these insults is manifested by its specific immune environment. The liver contains the tissue-resident macrophages called Kupffer cells, tissue-resident lymphocytes known as natural killer (NK) cells, NKT cells, conventional and unconventional immune cells namely αβ T cells, γδ T cells, and B cells which makes the liver an immunotolerant organ that limits the progression of chronic liver diseases such as liver cancers and cirrhosis (10). The conventional NK cells (cNKs) and tissue-resident innate lymphoid cells 1 (trILC1s) control the metastatic load in the liver but do not appear to have redundant effects. The cNKs and trILC1 cooperate in a non-redundant manner to control liver metastasis and the metastatic niche affects each innate subset differently in a cancer-type-specific manner (11). Thus, understanding the physiology of the liver is a prerequisite to understanding the pathological or immunological condition of the HCC patients.
In humans, extrahepatic and intrahepatic cells, as the main cells of our innate immune system, play a significant role in the body’s immune response to cells infected with different viruses such as HBV or HCV, as well as tumors such as HCC. These NK cells have multiple functions such as granzyme/perforin-mediated apoptosis, Fas/Fasl-mediated cell death, production and secretion of different types of cytokines, and cytokine activation of NK and cytotoxic T lymphocytes (Figure 1) (12, 13). All extrahepatic and intrahepatic cells communicate with each other in a coordinated manner to keep the normal homeostasis of the immune system.
Figure 1 The general overview of the role of NK cells in HCC and HBV-induced HCC. An overview of important cells, cytokines, ligands, and their receptors involved in HCC growth and development. As an important part of our immune system, NK cells play an important role in different stages of HCC development. Their functions are mainly regulated by interactions with other immune cells such as macrophages and dendritic cells, which are mediated by different types of cytokines, ligands, and their receptors. Macrophages and dendritic cells stimulate NK cells by secreting pro-inflammatory cytokines such as IL-12, IL-15, and IL-18. Together with the above-mentioned cytokines and ligands, IL-2, type I IFN, and TLR ligands further stimulate and increase NK cell cytotoxicity. Upon activation, NK cells secrete pro-inflammatory cytokines and induce hepatic stellate cell apoptosis and HBV lysis using Fas/FasL and granzyme/perforin-mediated mechanisms. NKG2D is a significantly important receptor that is activated upon binding to its ligand MICA/B and subsequently leads to enhancing the cytotoxicity of NK cells and blocking STAT3. All of these lead to apoptosis of HCC cells and prevent HCC progression and metastasis.
Despite the availability of advanced therapeutic approaches and exhaustive research activities, most HCC patients still face a miserable HCC prognosis (14). Systematic palliative treatment is required for these patients which are comprised of tyrosine kinase inhibitors (TKI) such as sorafenib, regorafenib, and lenvatinib, and are employed as a first-line treatment option for HCC patients. Similarly, a human monoclonal antibody such as cabozantinib and ramucirumab explicitly targets vascular endothelial growth factor receptor type 2 (VEGF-R2) and is employed as a second-line treatment option for HCC patients (15–17). However, these systematic treatments yield superficial survival benefits and thus emphasize the need for new therapeutic approaches for HCC treatment (18). The current review will summarize the dynamic role of NK cells in different liver cancers particularly HCC and HBV-associated HCC and its therapeutic implications.
Natural Killer (NK) Cells as an Active Player in Innate Immune Response
NK cells are the main component of innate lymphoid cells (ILCs) that have a key role in immune defense mechanism, not only as an immunosurveillance, but also to play a cytotoxic role against different viral and transformed infected cells and produce chemokines and cytokines (19, 20). The frequency of NK cells decreases in the blood of Hepatitis B and C viral infection and increases in the liver (21). About 15% of all lymphocytes are comprised of human NK cells and phenotypically defined based on the presence of CD56 expression with the absence of CD3 expression and more than 30% proportion of NK cells solely found in the liver (22, 23). The activity of natural killer cells depends on inhibitory and activating signals communicated through a large number of surface receptors. The killing of healthy cells is prevented by NK cells through different inhibitory receptors, which include KIR, ILT2/CD85, and CD94/NKG2A (24–26). Activating receptors such as DNAM1, NKp46, NKp30, NKp44, and NKG2D identify self-proteins mainly expressed on stress target cells (27). All these receptors coordinate to maintain the normal homeostasis of natural killer cells.
NK cells function primarily by recognizing and killing target cells and secreting cytokines such as interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), which can control antiviral immune responses. NK cells also play a vital role in linking innate and adaptive immune responses by producing antiviral cytokines and chemokines (28). On the basis of CD56 cell membrane density, NK cells can be divided into two subpopulations, CD56bright and CD56dim. CD56dim NK cells express high levels of the low-affinity Fc receptors CD16 and killer immunoglobulin-like receptors (KIRs) and account for approximately 90% of all blood NK cells, whereas CD56bright NK cells account for less than 10% of all blood NK cells and do not express CD16 and KIR (29). Functionally, CD56dim NK cells proficiently kill target cells through degranulation but secrete low levels of cytokines; conversely, CD56bright NK cells produce large amounts of cytokines when stimulated but are less cytotoxic. However, CD56bright cells exhibited similar or enhanced cytotoxicity to target cells after prolonged activation compared to CD56dim cells (30). In addition, CD56bright NK cells constitutively express high- and intermediate-affinity interleukin 2 receptors (IL-2R) and increase in vitro and in vivo in response to low doses of IL-2 (31). On the contrary, resting CD56dim NK cells express only moderate-affinity IL-2R in vitro in a weak proliferative response to high doses of IL-2 even after induction of high-affinity IL-2R (32). Therefore, the NK cell is considered as one of the active players in maintaining the innate immune response of the body.
The Impact of Tumor Immune Microenvironment (TIME) on the Function of NK Cells and Biological Function of HCC
The intrahepatic microenvironment is crucial for NK cell permanency, proliferation, function, and persistence. The HCC microenvironment is a dynamic constituent of the tumor that supports passive structure for tumor development which fluctuates vigorously. Thus, affects the performance of HCC progression. These immunosuppressive landscapes of HCC represent a perplexing hurdle for clinicians to propose operational immunotherapies for liver cancer. The HCC microenvironment is not only comprised of stroma-produced growth factors, metabolites, chemokines and cytokines, and tumor cells, but also tumor-infiltrating macrophages, myeloid-derived suppressor cells, neutrophils, cancer-associated fibroblasts, and regulatory T cells. They all play important roles in the clinical consequence and accomplishment or failure of HCC immunotherapy (23, 33).
Several immune cells perform various functions in the TIME of HCC. The Myeloid-derived suppressor cells (MDSCs) employ numerous mechanisms of immunosuppressive activity in the TME. MDSCs stimulate differentiation and development of Tregs during tumorigenesis; suppress NK and DCs cells through TGF-β, dispossess T cells of indispensable amino acids, such as L-cysteine and L-arginine, and produce oxidative stress that leads to HCC progression (Figure 2) (34, 35). Co-culture of MDSCs with autologous T cells stimulates enlarged Treg numbers, PD-1+ depleted T cells, and increased levels of immunosuppressive cytokines in HCC patients (36). MDSCs also suppressed the production of TLR ligand-stimulated IL-12 and suppressed the T-cell stimulating activity of DCs in HCC (37). MDSCs also weaken NK cell function. In HCC, MDSCs suppress cytotoxicity of NK cells and release cytokine-mediated via the NKp30 receptor (38). Tumor-associated neutrophils can recruit Treg cells and macrophages to HCC to stimulate its development and resistance to sorafenib treatment therapy (39, 40). Thus, MDSCs are involved in the regulation of tumor progression.
Figure 2 The Impact of Tumor Immune Microenvironment (TIME) on the function of NK cells and the biological function of HCC. MDSCs stimulate differentiation and development of Tregs during tumorigenesis; suppress NK and DCs cells through TGF-β, dispossess amino acids, such as L-cysteine and L-arginine, and produce oxidative stress and the microenvironment becomes hypoxic and leads to HCC progression.
Hepatic stellate cells (HSCs) are the main skeleton of HCC and can stimulate the proliferation of tumor cells. Conditioned media obtained from HSCs not only induce propagation and migration of HCC cells but also stimulate HCC growth by activating NFκB and extracellular regulated kinase (ERK) pathways (41). Cancer-associated fibroblasts are the predominant cell type within the tumor stroma and play a key role in tumor-stroma interactions (42). They are triggered via TGF-b and are liable for the removal, synthesis, and restoration of surplus extracellular matrix, thereby regulating the biological function of HCC. HCC cell extravasation, growth, and metastatic extent depend on the manifestation of these fibroblasts. HCC cells can mutually induce the propagation of tumor-associated fibroblasts, signifying their critical role in tumor-stroma interfaces (43). Stroma derived from HCC expresses numerous growth factors, including epidermal growth factor (EGF), hepatocyte growth factor (HGF), fibroblast growth factor (FGF), stromal-derived factor (SDF)-1a and IL-6, and members of the Wnt family (44). The TIME not only shapes the metabolism of NK cells but is also involved in effector function. Immunometabolic inhibition is critical for designing a new cohort of effective natural killer cell immunotherapies against solid tumors such as HCC. Numerous factors can restrain the metabolism of NK cells in the tumor microenvironment. HCC employs immunosuppressive activity through multiple mechanisms and a well-known driver is a hypoxia (45). The high oxygen depletion of tumor cells produces hypoxic regions. Hypoxia damages effector function of the NK cell but also maintains HIF1a, thereby promoting glycolytic metabolism (46). Hypoxia promotes the production of adenosine on antigen-presenting cells from the cancer-associated extracellular enzymes CD73 and CD39 (expressed on Treg) (47). Tumor cells also produce extracellular adenosine via the CD73 and CD39 and exonucleotidases, thereby impairing NK cell function by competing for nutrients (48). Human intratumoral CD96+ NK cells are functionally depleted in humans. Patients with higher intratumoral CD96 expression have the poorest clinical outcomes. Obstruction of CD96-CD155 interaction or TGF-β1 reestablishes NK cell immunity to tumors through reversing NK cell depletion, signifying a promising therapeutic role for CD96 in combating liver cancer (49). Therefore, it is important to understand the function of NK cells in the tumor immune microenvironment to fully understand the biological role of HCC.
The Dynamic Role of NK Cells in Liver Carcinoma
Role of NK Cells in HCC
HCC is immunologically cold as compared to other liver cancers that are only about 25% of immunoactive phenotypes (50, 51). The number of NK cells in HCC induced individuals is lower within the periphery and functionally inactive. NK cells exist less frequently as compared to myeloid and other lymphocytes within the tumors (52). As compared to peritumoral tissue, HCC accumulation of NK cells in intratumoral tissue has increased expression of CD56brigh: CD56dim ratios with enhanced expression of activation marker CD49A show local differences in these two smart microenvironments (53). The frequency and enhanced cytokine secretory function and increased cytotoxicity of NK cells in individuals have enhanced overall survival in HCCs after the liver resection (54, 55). The survival rate of patients is also positively correlated with the occurrence of intratumoral and circulating NK cells in HCC patients, and according to previous studies, the higher the frequency of intratumoral NK cells, the better the response of sorafenib therapy (55–57). A previous study revealed that sorafenib also acts through direct immunomodulation, which is essential for its antitumor activity. In vivo and mouse models of HCC identify macrophages (MΦs) as key mediators of antitumor effects and reveal that MΦs and NK cells are strongly interdependent in efficiently killing tumor cells. Additionally, sorafenib was found to downregulate the expression of major histocompatibility complex class-I (MHC-1) of tumor cells which might diminish tumor response to immune checkpoint therapy and favor NK cell response (58).
NK cells perform various functions in HCC related individuals to release cytokines. It was previously considered that IL-6 promotes elliptical cell proliferation and regeneration while TNF-α did not do so. Therefore, the lack of IL-6 results in a significant increase in the development of HCC along with a reduced level of NK cells. This indicates that IL-6 is responsible for NK cell-mediated HCC suppression but has not elucidated a potential mechanism (59–61). IL-1α has a variety of forms in vivo and each form has a different function. Membrane IL-1α suppresses the growth of HCC by stimulating T and NK cells while enhancing cytotoxic NK and T cell cytotoxicity (62). Generally, the release of membrane IL-1α and IL-6 increased the protection of HCC through NK cell-related mechanisms (63). In addition, these cytokines may have a vital role in obstacles related to HBV infection, such as HCC and cirrhosis, showing NK cells in the development of HCC (64, 65). Many activated NK cell receptors are related to HCC. Differential splicing in NKP30 results to generate suppressive isoforms that prevail in advanced HCC (66). However, most of the research has focused on NKG2D, which involves a number of ligands elements including UL16-binding proteins (ULBPs) and MHC-I related chain molecule A and B (MICA/B) proteins. These stress-induced proteins are expressed on tumors and can be secreted into the circulation by subsequent proteolytic cleavage, through molecules comprising ADAM9, which is upregulated in HCC (67). Soluble receptors found on the surface of NK cells bind and involve in the downregulation of NKG2D, therefore, making the cells less active. In HCC, high levels of soluble ULBP1 are related to poor survival (68). NKG2D can drive tumors in HCC mouse models, which may promote the intricacy of the molecular pathology of this disease by promoting mutagenic chronic inflammation. However, the downregulation of the NKG2D ligand axis ratio is related to the poor outcome of the disease (69, 70). Therefore, NK cells play an important role in pathogenesis of HCC.
Role of NK Cells in HBV Induced HCC
NK cells play a vital role in HBV-induced HCC. HBV acts as a stealth virus inside the hepatocytes and NK cells are used as two-edged swords of chronic HBV infection (71). NK cells are hepatoprotective and anti-fibrotic, while activation of NK cells arbitrates HBV-related hepatocyte injury. Recent studies have shown that IFN-γ derived from NK cells induced HCC through the epithelial cell adhesion molecule–epithelial-to-mesenchymal transition axis in HBV transgenic mice, and hepatitis B surface antigen (HBsAg)-positive hepatocyte damage was facilitated through activated NK cells, which stimulated the HCC development (72, 73). NK cells are related to early anti-tumor and antiviral properties (74). Inflammatory cells yield diverse cytokines and chemokines that regulate HBV-induced HCC tumors (Figure 1). The specific blocking of interleukin (IL)-10 and transforming growth factor (TGF)-β resumed an immunosuppressive environment in patients with chronic HBV infection by reducing anti-viral efficacy of NK cells (75, 76). Transmission of HBV in NK cells is regulated through HBV positive exosomes, which induces damage to NK cell function, including production of interferon (IFN) -γ, cell solubility, proliferation, and survival of NK cells (77). Further, the expression of miRNA-146A was increased in NK cells from HBV-induced HCC patients as compared to healthy individuals. The cytotoxicity of NK cells and production of IFN-γ and TNF-α of HBV-induced HCC patients were reduced as compared to healthy individuals (78). Therefore, NK cells along with different cytokines and chemokines play a significant role in HBV induced HCC.
In HBV-induced HCC, NK cells have always played a differing role because they employ antiviral and immunomodulatory functions while contributing to the pathogenesis of liver injury. The apoptosis of HBV-infected hepatocytes is conducive to self-protection because it helps clearance of virus from hepatocytes (79). However, in the case of continuous infection, the sustained injury of the liver is the premise of liver fibrosis and HCC. In the immunoactive stage of chronic hepatitis B (CHB), NK cells are biased towards cytolytic activity, which is positively correlated with the severity of the liver injury. Increased NK cell cytolytic activity can be partially ascribed to the change of certain cytokines and the identification between NKG2D and their ligands (80, 81).
NK cells are responsible to employ antiviral effects via perforin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) dependent cytolysis of infected cells and stimulation of IFN-γ production (82, 83). Phenotypic heterogeneity of NK cells has been described among HBV-induced HCC patients. It had increased expression levels of activating receptor NKG2D and a reduction in the inhibitory receptor, while the percentage of activating NKG2C+ NK cells amplified and the inhibitory receptor expression was normal in chronic HBV patients (84, 85),. It is believed that NK cells decreased in patients with chronic viral hepatitis patients to promote disease progression and conversion to HCC. In acute HCV infection, hepatic NK cells showed an increase in NKP46 expression and potentially degranulate and stimulate IFN-γ that subsequently activate IFN-α/β and other cytokines (IL-12, IL-15, IL-18) (Figure 1) (86, 87). NK cell repertoire in HBV patients co-infected with HCV is influenced towards memory-like phenotype related to enhanced CD16 mediated ADCC effector function. Even though liver NK cells sustain their cytotoxic role in chronic HBV infection through the upregulation of TRAIL, they eradicate autologous HBV specific CD8+ T cells expressing elevated levels of death receptor for TRAIL (88, 89). Thus, NK cells are indispensable to play a vital role in antiviral and immunomodulation in HBV-induced HCC.
NK Cell-Based Therapeutic Approaches
NK cells, as the main immunomodulatory constituent of our immune system, can directly kill tumor cells without antigen sensitization. A previous study indicated the prospective of cancer immunotherapy to control the activation of NK cells (90). Therefore, directly targeting NK cells can serve as a promising therapeutic strategy that can considerably improve the therapeutic process. (Table 1)
Table 1 NK Cell based Therapeutic Approaches.
Chemotherapeutic Approaches
A number of chemotherapeutic approaches and agents have been discovered to affect NK cells. The polysaccharide SEP acting through TLR2/4 has been shown to stimulate T lymphocytes and natural killer cells. It also increased the antitumor activity of the pyrimidine antimetabolite gemcitabine (GEM) against HCC by activation of the NKG2D and DAP10/Akt pathways that lead to activation of NK cells. It is also hypothesized that upregulation of NKG2D increases the sensitivity of NK-92 cells to targeting their ligand MHC-I related chain molecule A (MICA) expressed on HepG2 cells. GEM enhances the cytolytic activity of NK-92 cells against HepG2 cells by inhibiting ADAM10 and upregulating MICA expression and reducing soluble MICA (sMICA) secretion (91, 92). Multi-targeted tyrosine kinase inhibitors (MTKIs) facilitate upregulation of NKG2D ligands, sensitizing cancer cells to natural killer cell therapy. However, the exact underlying mechanism remains unknown. Sunitinib is an MTKI shown to escalate the stimulation and cytotoxicity of natural killer cells in the HepG2 cell line. It leads to the upregulation of NKG2DLs through non-canonical pathways of NF-kB signaling, apoptotic, and DNA damage repair genes (93). Muromonab-CD3, an anti-CD3 antibody, together with the alternative GMP-CD3 with similar effects on hepatic monocytes, causes enhanced natural killer cell activation and T lymphocyte exhaustion (94). Administration of sorafenib initiates the pro-inflammatory activity of tumor-associated macrophages by sensitizing them to exogenous immune stimulation. This results in the stimulation of antitumor natural killer cell responses in a cytokine and NF-kB dependent manner. Activation of natural killer cells triggered through sorafenib is dependent on the activity of LPS, an exogenous factor that can be present profusely in the hepatic portal system (95). A previous study reveals that sorafenib may enhance cytotoxicity by suppressing AR, thereby enhancing a subtype of IL-12 and IL-12A (96, 97). Regorafenib is a newly discovered multi-kinase inhibitor anticancer drug for the treatment of advanced HCC and works by suppressing c-RAF, c-KIT, RET, TIE-2, PDGFR, BRAF, VEGFR1-3, FGFR-1, and p38 MAP kinases. Compared with sorafenib, regorafenib is more effective in inducing apoptosis in HCC cells but the toxicity and side effects are nearly the same (98, 136). A combination of different chemotherapeutics agents might be helpful for future treatment regimes.
CAR-NK Based Therapeutic Approaches
Numerous approaches have been established to expand the targeting and effectiveness of NK cell cytotoxicity against tumor cells using genetic alteration techniques. Strategies employed to generate chimeric antigen receptor-NK (CAR-NK) cells have also been applied that not only increase the efficacy of NK cell therapy but also largely escalate the specificity of NK cell therapy (137, 138). CARs are comprised of a single-chain extracellular variable fragment (scFv) and an intracellular immune cell activation domain (139, 140). Using CAR-T as a prototype model, preliminary studies on NK cells integrated the 4-1BB co-stimulatory domain, which confers greater persistence; however, 2B4 is an NK cell-specific co-stimulatory domain that improves cell function in a number of ways, including increased cytotoxicity, persistence, proliferation, and cytokine secretion (141). Previous studies revealed four different costimulatory domains (DAP10, DAP12, 2B4, and CD137) and four different transmembrane domains (NKp44, NKp46, CD16, and NKG2D) in combination with CD3ζ to enhance NK cell-specific CAR constructs. These studies validate that CARs containing the 2B4 costimulatory domain and NKG2D transmembrane domain mediate improved antitumor activity in vitro as well as in the ovarian cancer xenograft model (142). Furthermore, CAR experiments using PB-NK showed that subpopulations responded differently to CAR stimulation, with terminally differentiated NK cells exhibiting the best response. Moreover, this observation was only tested against the anti-CD19 ectodomain. Determining which subpopulations respond best to modifications in other ectodomains requires further investigation (143). This point confirms that the benefits of using multiple CAR-NK cell populations can be produced for the optimization of cancer therapy.
CAR-NK cells are primary NK cells genetically engineered to express a chimeric antigen receptor (CAR), such as glypican-3 (GPC3) or alpha-fetoprotein (AFP), that promotes the binding of relevant antigens in a specific manner. In addition, NK cells express receptors for the Fc portion of immunoglobulins (FcRs) that bind to target cells and mediate cytolysis of NK cell susceptible target cells (i.e., antibody-dependent cell cytotoxicity ADCC) (144). Among genetically altered NK cells, GPC3 specific CAR-NK-92 cells have been reported to have high antitumor activity against HCC xenografts expressing high and low levels of GPC3. The specificity of GPC3 CAR-NK-92 cells was confirmed by the potent cytolytic activity shown in an in vitro cytotoxicity assay against GPC3+ HCC cells, whereas no cytotoxicity was observed in GPC3- HCC cells. Therefore, GPC3-specific CAR-NK cells represent a new therapeutic approach for GPC3+ HCC patients (99). NK and T cells are transduced with a CAR that recognizes basigin (the surface marker CD147) that not only kills several malignant HCC cell lines in vitro but also kills HCC tumors in xenograft and patient-derived xenograft mouse models (100). These findings represent the therapeutic potential of CD147-CAR-modified immune cells in HCC patients.
iPSC-NK Cell Based Therapeutic Approaches
Several studies have genetically engineered induced pluripotent stem cells (iPSCs) to generate iPSC-NK cells with in vivo persistence and improved expansion. Many of these techniques were first developed and tested in cord blood-NK (CB-NK) cells and peripheral blood-NK (PB-NK) cells and successively transformed into iPSC-derived NK cells. The iPSCs offer a stable platform for a routine genetic alteration process that only needs to be done in a one-time. Once stably engineered iPSC clones are identified, they can be extended and used to generate standardized populations of properly engineered iPSCs derived NK cells (101, 102). The interleukine-15 (IL-15) plays an important role in stimulating NK cell expansion and cytotoxic function (103, 104). Activation of IL-15 was also revealed to alleviate immunosuppression mediated through transforming growth factor (TGF)-b1 released by the TME. These features make manipulation of IL-15 expression an attractive approach to increase the antitumor activity of various NK cell populations without the need to supplement cell-producing cultures with high doses of cytokines (105). A study conducted by Imamura et al. confirmed that expression of a membrane-bound form of IL-15 (mbIL-15) in human PB-NK cells enhances antitumor killing against hematological malignancies and solid tumors by increasing the survival of NK cells and expanded in vitro and in vivo without additional exogenous cytokines (106). Another method adopted by two different groups to increase the antitumor activity of iPSC-NK and PB-NK cells in vitro and in vivo using an IL-15 receptor fusion construct consisting of an IL-15 receptor alpha and IL-15 superagonist (IL-15RA/IL15SA), respectively (107, 108). By employing these approaches, the antitumor activity could be enhanced with greater efficacy.
A broader range of effector functions can be achieved by treating NK cells with cytokines (109). In preclinical and clinical studies, the different groups showed that treatment with a cytokine cocktail consisting of IL-12, IL-15, and IL-18 resulted in the development of cytokine-induced memory like-NK (CIML-NK) cells and enhanced interferon-g (IFN-g) generation and cytotoxicity against leukemia cell lines or primary human AML blasts (110, 111). Their Phase I clinical trial resulted in complete remission in 4 of 9 patients (112). The CIML-NK cells further exhibit enhanced IFN-g production, enhanced cytotoxicity, and persistence against ovarian cancer and other malignancies (113, 114). Different bispecific engager molecules are also involved in therapeutic approaches. The blinatumomab is a CD3-CD19 bispecific antibody that binds and transports CD3+ T cells to CD19+ B-cell in acute lymphoblastic leukemia and several groups have developed multivalent targeting molecules that specifically engage in the vicinity of the target tumor NK cells to enhance tumor killing (115). These Bispecific Killer engagers (BiKEs) or Trispecific Killer engagers (TriKEs) are designed to stimulate NK cells that subsequently activate cell surface cell receptors. For instance, engagers targeting NK cells for CD30+ lymphoma, CD133+ colon cancer, CD33+ myelodysplastic syndrome, CLEC12A+ and CD33+ acute myeloid cell (AML) are all in clinical development. A bispecific CD30xCD16 engager direct CB-NK and PB-NK cells to escalate cytotoxicity against CD30+ Lymphoma in in vitro and in vivo in preclinical studies (116). A CD16xCD33 bispecific engager and TriKE targeting CD16, CD33, and stimulating IL15 improve NK cell killing of CD33+ myelodysplastic syndrome cells (117, 118). NK cells more efficiently kill CD133+ or EPCAM+ colon cancer cells via CD16xCD133 or CD16xEpcam TriKE containing an IL-15 cross-linker (119, 120). The BiKEs and TriKEs targeting CD33 and CLEC2A on AML increased NK cell-mediated killing of CD33+ or CLEC2A+ AML cells, respectively, in preclinical models of AML (121, 122). Clinical trials employing these engineered iPSC-NK cells are underway that could be a benefit in near future.
Immunotherapeutic Approaches
TRAIL is immunoprotective by enhancing the infiltration of natural killer cells in the tumor environment. TRAIL-expressing NK cells are characteristically reduced by decreased expression of the CXCR3 ligand CXCL9 after hepatectomy. Both hepatectomy and partial hepatectomy lead to downregulation of the CXCL9-CXCR3 axis, resulting in a reduction of TRAIL-expressing NK cells, which is associated with poor prognosis and early HCC recurrence (123). However, new studies have also revealed the combination of oncolytic adenoviruses encoding IL-12 and TRAIL genes can inhibit hepatocellular carcinoma via enhancing the infiltration of NK cells in the tumor microenvironment. Therefore, stimulation of TRAIL after hepatectomy to improve diagnostic outcomes has great therapeutic potential (124). Different cytokines agonists such as TLR7 and TLR8 agonists can also enhance the efficiency of NK cell-based immune surveillance through stimulating NK-DC crosstalk. DCs also lead to type I IFN and IL-12 dependent enhancement of NK cell function, resulting in an enhanced antitumor immune response to HCC. A previous study revealed that GPC3-specific chimeric AR-engineered NK cells have been developed with high cytotoxic activity as an effective immunotherapy option for GPC3+ HCC patients (99, 125). Peripheral blood natural killer cells can be extended and activated by using different types of proinflammatory cytokines such as IL-12, IL-21, IL-15, IL-2, and type I IFN (64). It was demonstrated previously that natural killer cells generally had higher levels of cytotoxicity against HCC cell lines than unstimulated or IL-2-activated NK cells. Furthermore, experiments showed that the use of the chimeric NKG2D-CD3ζ-DAP10 receptor increased the signaling capability of the NKG2D receptor, resulting in the increased cytotoxic activity of the expanded natural killer cells in vitro and an immunodeficient mouse model (126). Immunotherapeutic agents with the combination of different cytokines agonists can be helpful in enhancing the efficiency of NK cell-based immune surveillance.
Antimicrobials and Novel Treatments
Recent studies have revealed the possibility of using existing antibacterial agents to treat HCC. Anisomycin is an antibiotic and an inhibitor of eukaryotic protein synthesis produced by Streptomyces griseolus. It has shown potential as a novel therapeutic HCC drug in the previous study, as it controls a wide range of genes, such as CD58, ICAM4, lymphocyte-associated antigen 3, and MHC-1 to improve immunity and acts as an immunological synapse between HCC and natural killer cells (127, 128). Lomofungin is an FDA-approved antifungal agent that reduces the activity of ADAM17 and then reduces sMICA activity in a dose-dependent manner (129, 130). The antifungal drug histone deacetylase inhibitors (HDACI) trichostatin A indirectly kills HCC cells by enhancing cytotoxicity of NK cells in HCC through transcriptional regulation of important genes such as RAET1G and ULBP1 leads to directly enhancing apoptosis of HCC cells (131). Thus, existing antimicrobial agents have shown promising potential in the systematic treatment of HCC.
Some novel treatment has been proposed for the treatment of HCC. Gastrodin is a compound extracted from the famous East Asian nourishing food Gastrodiaelata Blume. It can ease the low-toxic growth of transplanted H22 liver tumor cells in mice. Gastrodin causes increased cytotoxicity of natural killer cells and CD8+ T lymphocytes through a mechanism that is poorly understood (132). Mellitin has potential antitumor, antibacterial, antiarthritic, and anti-inflammatory characteristics usually isolated from bee venom. The TT-1, a synthetic novel peptide analog, was developed with more antitumor effects. The combination of IFN-α and TT-1 enhanced the activity of NK cells against HCC cells by stimulating interaction between MICA and NKG2D (133, 134). Another melittin analog, Mel-P15, was also considered to have potential in HCC treatment. It directly initiates cytotoxicity of NK cells and potentiates TNF-α, IFN-γ, and IL-2 secretion (135). Therefore, different antimicrobial agents and novel treatment regimens could be employed for HCC treatment.
Conclusion
NK cells play a vital role in HCC and inhibit the development of liver fibrosis, cirrhosis, and hepatocarcinogenesis. NK cell-based anti-HCC therapeutic approaches are becoming increasingly attractive. However, most attempts are being explored in animal models or ongoing human clinical trials. The evaluation of long-term antitumor effect and safety requires further observation. A deeper understanding of the mechanisms by which NK cells recognize tumors and HCC evade NK cells in a liver-specific microenvironment will provide valuable insights into the treatment of HCC. The selection of NK cells with predominantly activating properties is critical to providing successful anti-HCC activity. Immunotherapy based on specific NK subsets, especially liver-specific NK cells, may be attractive for HCC patients. Importantly, the strategy of combining NK cell-based immunotherapy with conventional chemotherapy or other multiple therapies will offer greater hope for persistent patients with HCC and HBV-induced HCC.
Author Contributions
CS conceived and directed the project. MS and CS drafted the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by the National Key Research and Development Program of China (# 2021YFC2300600), National Natural Science Foundation of China (# 8202290021, # 92169118, #91942310) and Anhui Provincial Natural Science Foundation (# 2008085J35).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Abdelrahman MM, Fawzy IO, Bassiouni AA, Gomaa AI, Esmat G, Waked I, et al. Enhancing NK Cell Cytotoxicity by miR-182 in Hepatocellular Carcinoma. Hum Immunol (2016) 77:667–73. doi: 10.1016/j.humimm.2016.04.020
2. Juengpanich S, Shi L, Iranmanesh Y, Chen J, Cheng Z, Khoo AK-J, et al. The Role of Natural Killer Cells in Hepatocellular Carcinoma Development and Treatment: A Narrative Review. Transl Oncol (2019) 12:1092–107. doi: 10.1016/j.tranon.2019.04.021
3. Yarchoan M, Agarwal P, Villanueva A, Rao S, Dawson LA, Karasic T, et al. Recent Developments and Therapeutic Strategies Against Hepatocellular Carcinoma. Cancer Res (2019) 79:4326–30. doi: 10.1158/0008-5472.CAN-19-0803
4. McGlynn KA, Petrick JL, London WT. Global Epidemiology of Hepatocellular Carcinoma: An Emphasis on Demographic and Regional Variability. Clin Liver Dis (2015) 19:223–38. doi: 10.1016/j.cld.2015.01.001
5. Müller M, Bird TG, Nault J-C. The Landscape of Gene Mutations in Cirrhosis and Hepatocellular Carcinoma. J Hepatol (2020) 72:990–1002. doi: 10.1016/j.jhep.2020.01.019
6. Zhai W, Lim TK-H, Zhang T, Phang S-T, Tiang Z, Guan P, et al. The Spatial Organization of Intra-Tumour Heterogeneity and Evolutionary Trajectories of Metastases in Hepatocellular Carcinoma. Nat Commun (2017) 8:1–9. doi: 10.1038/ncomms14565
7. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A Global View of Hepatocellular Carcinoma: Trends, Risk, Prevention and Management. Nat Rev Gastroenterol Hepatol (2019) 16:589–604. doi: 10.1038/s41575-019-0186-y
8. Mokdad AH, Dwyer-Lindgren L, Fitzmaurice C, Stubbs RW, Bertozzi-Villa A, Morozoff C, et al. Trends and Patterns of Disparities in Cancer Mortality Among US Counties, 1980-2014. Jama (2017) 317:388–406. doi: 10.1001/jama.2016.20324
9. Wilkinson AL, Qurashi M, Shetty S. The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver. Front Physiol (2020) 11. doi: 10.3389/fphys.2020.00990
10. Giraud J, Chalopin D, Blanc J-F, Saleh M. Hepatocellular Carcinoma Immune Landscape and the Potential of Immunotherapies. Front Immunol (2021) 12699. doi: 10.3389/fimmu.2021.655697
11. Ducimetière L, Lucchiari G, Litscher G, Nater M, Heeb L, Nuñez NG, et al. Conventional NK Cells and Tissue-Resident ILC1s Join Forces to Control Liver Metastasis. Proc Natl Acad Sci (2021) 118:1–12. doi: 10.1073/pnas.2026271118
12. Nomura M, Tsuge M, Uchida T, Hiraga N, Kurihara M, Tsushima K, et al. CTL-Associated and NK Cell-Associated Immune Responses Induce Different HBV DNA Reduction Patterns in Chronic Hepatitis B Patients. J Viral Hepat (2018) 25:1555–64. doi: 10.1111/jvh.12970
13. Shabani Z, Bagheri M, Zare-Bidaki M, Hassanshahi G, Arababadi MK, Nejad MM, et al. NK Cells in Hepatitis B Virus Infection: A Potent Target for Immunotherapy. Arch Virol (2014) 159:1555–65. doi: 10.1007/s00705-013-1965-3
14. Roderburg C, Wree A, Demir M, Schmelzle M, Tacke F. The Role of the Innate Immune System in the Development and Treatment of Hepatocellular Carcinoma. Hepatic Oncol (2020) 7:HEP17. doi: 10.2217/hep-2019-0007
15. Ogasawara S, Chiba T, Ooka Y, Suzuki E, Maeda T, Yokoyama M, et al. Characteristics of Patients With Sorafenib-Treated Advanced Hepatocellular Carcinoma Eligible for Second-Line Treatment. Invest New Drugs (2018) 36:332–9. doi: 10.1007/s10637-017-0507-3
16. Kudo M, Finn RS, Qin S, Han K-H, Ikeda K, Piscaglia F, et al. Lenvatinib Versus Sorafenib in First-Line Treatment of Patients With Unresectable Hepatocellular Carcinoma: A Randomised Phase 3 non-Inferiority Trial. Lancet (2018) 391:1163–73. doi: 10.1016/S0140-6736(18)30207-1
17. Al-Salama ZT, Syed YY, Scott LJ. Lenvatinib: A Review in Hepatocellular Carcinoma. Drugs (2019) 79:665–74. doi: 10.1007/s40265-019-01116-x
18. Parikh ND, Singal AG, Hutton DW. Cost Effectiveness of Regorafenib as Second-Line Therapy for Patients With Advanced Hepatocellular Carcinoma. Cancer (2017) 123:3725–31. doi: 10.1002/cncr.30863
19. Artis D, Spits H. The Biology of Innate Lymphoid Cells. Nature (2015) 517:293–301. doi: 10.1038/nature14189
20. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or Adaptive Immunity? The Example of Natural Killer Cells. Science (2011) 331:44–9. doi: 10.1126/science.1198687
21. Rehermann B. Pathogenesis of Chronic Viral Hepatitis: Differential Roles of T Cells and NK Cells. Nat Med (2013) 19:859–68. doi: 10.1038/nm.3251
22. Doherty DG, Norris S, Madrigal-Estebas L, McEntee G, Traynor O, Hegarty JE, et al. The Human Liver Contains Multiple Populations of NK Cells, T Cells, and CD3+ CD56+ Natural T Cells With Distinct Cytotoxic Activities and Th1, Th2, and Th0 Cytokine Secretion Patterns. J Immunol (1999) 163:2314–21.
23. Bozward AG, Warricker F, Oo YH, Khakoo SI. Natural Killer Cells and Regulatory T Cells Cross Talk in Hepatocellular Carcinoma: Exploring Therapeutic Options for the Next Decade. Front Immunol (2021) 12:1493. doi: 10.3389/fimmu.2021.643310
24. Kamiya T, Seow SV, Wong D, Robinson M, Campana D. Blocking Expression of Inhibitory Receptor NKG2A Overcomes Tumor Resistance to NK Cells. J Clin Invest (2019) 129:2094–106. doi: 10.1172/JCI123955
25. Long EO. Negative Signaling by Inhibitory Receptors: The NK Cell Paradigm. Immunol Rev (2008) 224:70–84. doi: 10.1111/j.1600-065X.2008.00660.x
26. Pegram HJ, Andrews DM, Smyth MJ, Darcy PK, Kershaw MH. Activating and Inhibitory Receptors of Natural Killer Cells. Immunol Cell Biol (2011) 89:216–24. doi: 10.1038/icb.2010.78
27. Lanier LL. NK Cell Recognition. Annu Rev Immunol (2005) 23:225–74. doi: 10.1146/annurev.immunol.23.021704.115526
28. Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, et al. Human Natural Killer Cells: A Unique Innate Immunoregulatory Role for the CD56bright Subset. Blood J Am Soc Hematol (2001) 97:3146–51. doi: 10.1182/blood.V97.10.3146
29. Cooper MA, Fehniger TA, Caligiuri MA. The Biology of Human Natural Killer-Cell Subsets. Trends Immunol (2001) 22:633–40. doi: 10.1016/S1471-4906(01)02060-9
30. Strowig T, Brilot F, Münz C. Noncytotoxic Functions of NK Cells: Direct Pathogen Restriction and Assistance to Adaptive Immunity. J Immunol (2008) 180:7785–91. doi: 10.4049/jimmunol.180.12.7785
31. Jost S, Altfeld M. Control of Human Viral Infections by Natural Killer Cells. Annu Rev Immunol (2013) 31:163–94. doi: 10.1146/annurev-immunol-032712-100001
32. Wu S, Wang W, Gao Y. Natural Killer Cells in Hepatitis B Virus Infection. Braz J Infect Dis (2015) 19:417–25. doi: 10.1016/j.bjid.2015.05.006
33. Osei-Bordom D, Bozward AG, Oo YH. The Hepatic Microenvironment and Regulatory T Cells. Cell Immunol (2020) 357:104195. doi: 10.1016/j.cellimm.2020.104195
34. De Cicco P, Ercolano G, Ianaro A. The New Era of Cancer Immunotherapy: Targeting Myeloid-Derived Suppressor Cells to Overcome Immune Evasion. Front Immunol (2020) 11:1680. doi: 10.3389/fimmu.2020.01680
35. Haist M, Stege H, Grabbe S, Bros M. The Functional Crosstalk Between Myeloid-Derived Suppressor Cells and Regulatory T Cells Within the Immunosuppressive Tumor Microenvironment. Cancers (Basel) (2021) 13:210. doi: 10.3390/cancers13020210
36. Kalathil S, Lugade AA, Miller A, Iyer R, Thanavala Y. Higher Frequencies of GARP+ CTLA-4+ Foxp3+ T Regulatory Cells And Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma Patients are Associated With Impaired T-Cell Functionality. Cancer Res (2013) 73:2435–44. doi: 10.1158/0008-5472.CAN-12-3381
37. Hu C-E, Gan J, Zhang R-D, Cheng Y-R, Huang G-J. Up-Regulated Myeloid-Derived Suppressor Cell Contributes to Hepatocellular Carcinoma Development by Impairing Dendritic Cell Function. Scand J Gastroenterol (2011) 46:156–64. doi: 10.3109/00365521.2010.516450
38. Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H, et al. Myeloid Derived Suppressor Cells Inhibit Natural Killer Cells in Patients With Hepatocellular Carcinoma via the NKp30 Receptor. Hepatology (2009) 50:799–807. doi: 10.1002/hep.23054
39. Zhou S, Yin D, Hu Z, Luo C, Zhou Z, Xin H, et al. A Positive Feedback Loop Between Cancer Stem-Like Cells and Tumor-Associated Neutrophils Controls Hepatocellular Carcinoma Progression. Hepatology (2019) 70:1214–30. doi: 10.1002/hep.30630
40. Zhou S-L, Zhou Z-J, Hu Z-Q, Huang X-W, Wang Z, Chen E-B, et al. Tumor-Associated Neutrophils Recruit Macrophages and T-Regulatory Cells to Promote Progression of Hepatocellular Carcinoma and Resistance to Sorafenib. Gastroenterology (2016) 150:1646–58. doi: 10.1053/j.gastro.2016.02.040
41. Amann T, Bataille F, Spruss T, Mühlbauer M, Gäbele E, Schölmerich J, et al. Activated Hepatic Stellate Cells Promote Tumorigenicity of Hepatocellular Carcinoma. Cancer Sci (2009) 100:646–53. doi: 10.1111/j.1349-7006.2009.01087.x
42. Kalluri R. The Biology and Function of Fibroblasts in Cancer. Nat Rev Cancer (2016) 16:582–98. doi: 10.1038/nrc.2016.73
43. Fransvea E, Mazzocca A, Antonaci S, Giannelli G. Targeting Transforming Growth Factor (TGF)-βri Inhibits Activation of β1 Integrin and Blocks Vascular Invasion in Hepatocellular Carcinoma. Hepatology (2009) 49:839–50. doi: 10.1002/hep.22731
44. Tripathi M, Billet S, Bhowmick NA. Understanding the Role of Stromal Fibroblasts in Cancer Progression. Cell Adh Migr (2012) 6:231–5. doi: 10.4161/cam.20419
45. Krzywinska E, Stockmann C. Hypoxia, Metabolism and Immune Cell Function. Biomedicines (2018) 6:56. doi: 10.3390/biomedicines6020056
46. Velásquez SY, Killian D, Schulte J, Sticht C, Thiel M, Lindner HA. Short Term Hypoxia Synergizes With Interleukin 15 Priming in Driving Glycolytic Gene Transcription and Supports Human Natural Killer Cell Activities. J Biol Chem (2016) 291:12960–77. doi: 10.1074/jbc.M116.721753
47. Synnestvedt K, Furuta GT, Comerford KM, Louis N, Karhausen J, Eltzschig HK, et al. Ecto-5′-Nucleotidase (CD73) Regulation by Hypoxia-Inducible Factor-1 Mediates Permeability Changes in Intestinal Epithelia. J Clin Invest (2002) 110:993–1002. doi: 10.1172/JCI0215337
48. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, et al. Adenosine Generation Catalyzed by CD39 and CD73 Expressed on Regulatory T Cells Mediates Immune Suppression. J Exp Med (2007) 204:1257–65. doi: 10.1084/jem.20062512
49. Sun H, Huang Q, Huang M, Wen H, Lin R, Zheng M, et al. Human CD96 Correlates to Natural Killer Cell Exhaustion and Predicts the Prognosis of Human Hepatocellular Carcinoma. Hepatology (2019) 70:168–83. doi: 10.1002/hep.30347
50. Weng J, Atyah M, Zhou C, Ren N. Prospects and Challenges of Circulating Tumor DNA in Precision Medicine of Hepatocellular Carcinoma. Clin Exp Med (2020) 20:329–37. doi: 10.1007/s10238-020-00620-9
51. Llovet JM, Montal R, Sia D, Finn RS. Molecular Therapies and Precision Medicine for Hepatocellular Carcinoma. Nat Rev Clin Oncol (2018) 15:599–616. doi: 10.1038/s41571-018-0073-4
52. Carrega P, Bonaccorsi I, Di Carlo E, Morandi B, Paul P, Rizzello V, et al. CD56brightperforinlow Noncytotoxic Human NK Cells Are Abundant in Both Healthy and Neoplastic Solid Tissues and Recirculate to Secondary Lymphoid Organs via Afferent Lymph. J Immunol (2014) 192:3805–15. doi: 10.4049/jimmunol.1301889
53. Sun H, Liu L, Huang Q, Liu H, Huang M, Wang J, et al. Accumulation of Tumor-Infiltrating CD49a+ NK Cells Correlates With Poor Prognosis for Human Hepatocellular Carcinoma. Cancer Immunol Res (2019) 7:1535–46. doi: 10.1158/2326-6066.CIR-18-0757
54. Wu M, Mei F, Liu W, Jiang J. Comprehensive Characterization of Tumor Infiltrating Natural Killer Cells and Clinical Significance in Hepatocellular Carcinoma Based on Gene Expression Profiles. BioMed Pharmacother (2020) 121:109637. doi: 10.1016/j.biopha.2019.109637
55. Cariani E, Pilli M, Barili V, Porro E, Biasini E, Olivani A, et al. Natural Killer Cells Phenotypic Characterization as an Outcome Predictor of HCV-Linked HCC After Curative Treatments. Oncoimmunology (2016) 5:e1154249. doi: 10.1080/2162402X.2016.1154249
56. Pinyol R, Montal R, Bassaganyas L, Sia D, Takayama T, Chau G-Y, et al. Molecular Predictors of Prevention of Recurrence in HCC With Sorafenib as Adjuvant Treatment and Prognostic Factors in the Phase 3 STORM Trial. Gut (2019) 68:1065–75. doi: 10.1136/gutjnl-2018-316408
57. Chew V, Chen J, Lee D, Loh E, Lee J, Lim KH, et al. Chemokine-Driven Lymphocyte Infiltration: An Early Intratumoural Event Determining Long-Term Survival in Resectable Hepatocellular Carcinoma. Gut (2012) 61:427–38. doi: 10.1136/gutjnl-2011-300509
58. Hage C, Hoves S, Strauss L, Bissinger S, Prinz Y, Pöschinger T, et al. Sorafenib Induces Pyroptosis in Macrophages and Triggers Natural Killer Cell–Mediated Cytotoxicity Against Hepatocellular Carcinoma. Hepatology (2019) 70:1280–97. doi: 10.1002/hep.30666
59. Yang Y, Ago T, Zhai P, Abdellatif M, Sadoshima J. Thioredoxin 1 Negatively Regulates Angiotensin II–induced Cardiac Hypertrophy Through Upregulation of miR-98/Let-7. Circ Res (2011) 108:305–13. doi: 10.1161/CIRCRESAHA.110.228437
60. Lu X, Xu C, Dong J, Zuo S, Zhang H, Jiang C, et al. Liraglutide Activates Nature Killer Cell-Mediated Antitumor Responses by Inhibiting IL-6/STAT3 Signaling in Hepatocellular Carcinoma. Transl Oncol (2021) 14:100872. doi: 10.1016/j.tranon.2020.100872
61. Wu J, Gao F, Wang C, Qin M, Han F, Xu T, et al. IL-6 and IL-8 Secreted by Tumour Cells Impair the Function of NK Cells via the STAT3 Pathway in Oesophageal Squamous Cell Carcinoma. J Exp Clin Cancer Res (2019) 38:1–15. doi: 10.1186/s13046-019-1310-0
62. Tawfik AK, Amin AM, Yousef M, El-Sayd NM, Elashry H, Elkadeem M, et al. IL-1α Correlates With Severity of Hepatitis C Virus-Related Liver Diseases. J Inflammation Res (2018) 11:289. doi: 10.2147/JIR.S166564
63. Lin G, Wang J, Lao X, Wang J, Li L, Li S, et al. Interleukin-6 Inhibits Regulatory T Cells and Improves the Proliferation and Cytotoxic Activity of Cytokine-Induced Killer Cells. J Immunother (2012) 35:337–43. doi: 10.1097/CJI.0b013e318255ada3
64. Tatsumi T, Takehara T. Impact of Natural Killer Cells on Chronic Hepatitis C and Hepatocellular Carcinoma. Hepatol Res (2016) 46:416–22. doi: 10.1111/hepr.12619
65. Tosello-Trampont A, Surette FA, Ewald SE, Hahn YS. Immunoregulatory Role of NK Cells in Tissue Inflammation and Regeneration. Front Immunol (2017) 8:301. doi: 10.3389/fimmu.2017.00301
66. Mantovani S, Oliviero B, Lombardi A, Varchetta S, Mele D, Sangiovanni A, et al. Deficient Natural Killer Cell NKp30-Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma. Hepatology (2019) 69:1165–79. doi: 10.1002/hep.30235
67. Kohga K, Takehara T, Tatsumi T, Ishida H, Miyagi T, Hosui A, et al. Sorafenib Inhibits the Shedding of Major Histocompatibility Complex Class I–related Chain A on Hepatocellular Carcinoma Cells by Down-Regulating a Disintegrin and Metalloproteinase 9. Hepatology (2010) 51:1264–73. doi: 10.1002/hep.23456
68. Easom NJW, Marks M, Jobe D, Gillmore R, Meyer T, Maini MK, et al. ULBP1 Is Elevated in Human Hepatocellular Carcinoma and Predicts Outcome. Front Oncol (2020) 971. doi: 10.3389/fonc.2020.00971
69. Sheppard S, Guedes J, Mroz A, Zavitsanou A-M, Kudo H, Rothery SM, et al. The Immunoreceptor NKG2D Promotes Tumour Growth in a Model of Hepatocellular Carcinoma. Nat Commun (2017) 8:1–13. doi: 10.1038/ncomms13930
70. Sheppard S, Ferry A, Guedes J, Guerra N. The Paradoxical Role of NKG2D in Cancer Immunity. Front Immunol (2018) 1808. doi: 10.3389/fimmu.2018.01808
71. Maini MK, Peppa D. NK Cells: A Double-Edged Sword in Chronic Hepatitis B Virus Infection. Front Immunol (2013) 4:57. doi: 10.3389/fimmu.2013.00057
72. Liu P, Chen L, Zhang H. Natural Killer Cells in Liver Disease and Hepatocellular Carcinoma and the NK Cell-Based Immunotherapy. J Immunol Res (2018) 2018:1–8. doi: 10.1155/2018/1206737
73. Chen Y, Hao X, Sun R, Wei H, Tian Z. Natural Killer Cell–Derived Interferon-Gamma Promotes Hepatocellular Carcinoma Through the Epithelial Cell Adhesion Molecule–Epithelial-To-Mesenchymal Transition Axis in Hepatitis B Virus Transgenic Mice. Hepatology (2019) 69:1735–50. doi: 10.1002/hep.30317
74. He Y, Tian Z. NK Cell Education via Nonclassical MHC and non-MHC Ligands. Cell Mol Immunol (2017) 14:321–30. doi: 10.1038/cmi.2016.26
75. Cho H-J, Cheong J-Y. Role of Immune Cells in Patients With Hepatitis B Virus-Related Hepatocellular Carcinoma. Int J Mol Sci (2021) 22:8011. doi: 10.3390/ijms22158011
76. Peppa D, Micco L, Javaid A, Kennedy PTF, Schurich A, Dunn C, et al. Blockade of Immunosuppressive Cytokines Restores NK Cell Antiviral Function in Chronic Hepatitis B Virus Infection. PloS Pathog (2010) 6:e1001227. doi: 10.1371/journal.ppat.1001227
77. Yang Y, Han Q, Hou Z, Zhang C, Tian Z, Zhang J. Exosomes Mediate Hepatitis B Virus (HBV) Transmission and NK-Cell Dysfunction. Cell Mol Immunol (2017) 14:465–75. doi: 10.1038/cmi.2016.24
78. Xu D, Han Q, Hou Z, Zhang C, Zhang J. miR-146a Negatively Regulates NK Cell Functions via STAT1 Signaling. Cell Mol Immunol (2017) 14:712–20. doi: 10.1038/cmi.2015.113
79. Zhang Z, Zhang S, Zou Z, Shi J, Zhao J, Fan R, et al. Hypercytolytic Activity of Hepatic Natural Killer Cells Correlates With Liver Injury in Chronic Hepatitis B Patients. Hepatology (2011) 53:73–85. doi: 10.1002/hep.23977
80. Zuo W, Zhao X. Natural Killer Cells Play an Important Role in Virus Infection Control: Antiviral Mechanism, Subset Expansion and Clinical Application. Clin Immunol (2021) 227:108727. doi: 10.1016/j.clim.2021.108727
81. Chen Y, Wei H, Sun R, Dong Z, Zhang J, Tian Z. Increased Susceptibility to Liver Injury in Hepatitis B Virus Transgenic Mice Involves NKG2D-Ligand Interaction and Natural Killer Cells. Hepatology (2007) 46:706–15. doi: 10.1002/hep.21872
82. Rehermann B. Natural Killer Cells in Viral Hepatitis. Cell Mol Gastroenterol Hepatol (2015) 1:578–88. doi: 10.1016/j.jcmgh.2015.09.004
83. Kalathil SG, Thanavala Y. Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches. Cells (2021) 10:1332. doi: 10.3390/cells10061332
84. Oliviero B, Varchetta S, Paudice E, Michelone G, Zaramella M, Mavilio D, et al. Natural Killer Cell Functional Dichotomy in Chronic Hepatitis B and Chronic Hepatitis C Virus Infections. Gastroenterology (2009) 137:1151–60. doi: 10.1053/j.gastro.2009.05.047
85. Song T, Li L, Su B, Liu L, Liu Y, Yang X, et al. NKG2C+ Natural Killer Cell Function Improves the Control of HBV Replication in Individuals With Acute HIV Infection Coinfected With HBV. Med (Baltimore) (2020) 99:1–12. doi: 10.1097/MD.0000000000020073
86. Amadei B, Urbani S, Cazaly A, Fisicaro P, Zerbini A, Ahmed P, et al. Activation of Natural Killer Cells During Acute Infection With Hepatitis C Virus. Gastroenterology (2010) 138:1536–45. doi: 10.1053/j.gastro.2010.01.006
87. Bozzano F, Picciotto A, Costa P, Marras F, Fazio V, Hirsch I, et al. Activating NK Cell Receptor Expression/Function (NKp30, NKp46, DNAM-1) During Chronic Viraemic HCV Infection Is Associated With the Outcome of Combined Treatment. Eur J Immunol (2011) 41:2905–14. doi: 10.1002/eji.201041361
88. Peppa D, Gill US, Reynolds G, Easom NJW, Pallett LJ, Schurich A, et al. Up-Regulation of a Death Receptor Renders Antiviral T Cells Susceptible to NK Cell–Mediated Deletion. J Exp Med (2013) 210:99–114. doi: 10.1084/jem.20121172
89. Oliviero B, Mantovani S, Varchetta S, Mele D, Grossi G, Ludovisi S, et al. Hepatitis C Virus-Induced NK Cell Activation Causes Metzincin-Mediated CD16 Cleavage and Impaired Antibody-Dependent Cytotoxicity. J Hepatol (2017) 66:1130–7. doi: 10.1016/j.jhep.2017.01.032
90. Qin Z, Chen J, Zeng J, Niu L, Xie S, Wang X, et al. Effect of NK Cell Immunotherapy on Immune Function in Patients With Hepatic Carcinoma: A Preliminary Clinical Study. Cancer Biol Ther (2017) 18:323–30. doi: 10.1080/15384047.2017.1310346
91. Xie X, Zhou Y, Wang X, Guo J, Li J, Fan H, et al. Enhanced Antitumor Activity of Gemcitabine by Polysaccharide-Induced NK Cell Activation and Immune Cytotoxicity Reduction In Vitro/Vivo. Carbohydr Polym (2017) 173:360–71. doi: 10.1016/j.carbpol.2017.06.024
92. Van der Meer JMR, de Jonge PKJD, van der Waart AB, Geerlings AC, Moonen JP, Brummelman J, et al. CD34+ Progenitor-Derived NK Cell and Gemcitabine Combination Therapy Increases Killing of Ovarian Cancer Cells in NOD/SCID/IL2Rgnull Mice. Oncoimmunology (2021) 10:1981049. doi: 10.1080/2162402X.2021.1981049
93. Huang Y, Chen X, Guo K, Li Y, Wu B, Song C, et al. Sunitinib Induces NK-κb-Dependent NKG2D Ligand Expression in Nasopharyngeal Carcinoma and Hepatoma Cells. J Immunother (2017) 40:164–74. doi: 10.1097/CJI.0000000000000168
94. Ohira M, Nishida S, Matsuura T, Muraoka I, Tryphonopoulos P, Fan J, et al. Comparative Analysis of T-Cell Depletion Method for Clinical Immunotherapy—Anti–Hepatitis C Effects of Natural Killer Cells via Interferon-γ Production. Transplant Proc Elsevier (2013) 45:2045–50. doi: 10.1016/j.transproceed.2013.01.046
95. Sprinzl MF, Reisinger F, Puschnik A, Ringelhan M, Ackermann K, Hartmann D, et al. Sorafenib Perpetuates Cellular Anticancer Effector Functions by Modulating the Crosstalk Between Macrophages and Natural Killer Cells. Hepatology (2013) 57:2358–68. doi: 10.1002/hep.26328
96. Ho V, Lim TS, Lee J, Steinberg J, Szmyd R, Tham M, et al. TLR3 Agonist and Sorafenib Combinatorial Therapy Promotes Immune Activation and Controls Hepatocellular Carcinoma Progression. Oncotarget (2015) 6:27252. doi: 10.18632/oncotarget.4583
97. Shi L, Lin H, Li G, Jin R-A, Xu J, Sun Y, et al. Targeting Androgen Receptor (AR)→ IL12A Signal Enhances Efficacy of Sorafenib Plus NK Cells Immunotherapy to Better Suppress HCC Progression. Mol Cancer Ther (2016) 15:731–42. doi: 10.1158/1535-7163.MCT-15-0706
98. Zhang Q, Zhang H, Ding J, Liu H, Li H, Li H, et al. Combination Therapy With EpCAM-CAR-NK-92 Cells and Regorafenib Against Human Colorectal Cancer Models. J Immunol Res (2018) 2018:1–11. doi: 10.1155/2018/4263520
99. Yu M, Luo H, Fan M, Wu X, Shi B, Di S, et al. Development of GPC3-Specific Chimeric Antigen Receptor-Engineered Natural Killer Cells for the Treatment of Hepatocellular Carcinoma. Mol Ther (2018) 26:366–78. doi: 10.1016/j.ymthe.2017.12.012
100. Tseng H, Xiong W, Badeti S, Yang Y, Ma M, Liu T, et al. Efficacy of Anti-CD147 Chimeric Antigen Receptors Targeting Hepatocellular Carcinoma. Nat Commun (2020) 11:1–15. doi: 10.1038/s41467-020-18444-2
101. Goodridge JP, Mahmood S, Zhu H, Gaidarova S, Blum R, Bjordahl R, et al. FT596: Translation of First-of-Kind Multi-Antigen Targeted Off-the-Shelf CAR-NK Cell With Engineered Persistence for the Treatment of B Cell Malignancies. Blood (2019) 134:301. doi: 10.1182/blood-2019-129319
102. Bjordahl R, Gaidarova S, Woan K, Cichocki F, Bonello G, Robinson M, et al. FT538: Preclinical Development of an Off-the-Shelf Adoptive NK Cell Immunotherapy With Targeted Disruption of CD38 to Prevent Anti-CD38 Antibody-Mediated Fratricide and Enhance ADCC in Multiple Myeloma When Combined With Daratumumab. Blood (2019) 134:133. doi: 10.1182/blood-2019-131138
103. Miller JS, Lanier LL. Natural Killer Cells in Cancer Immunotherapy. Annu Rev Cancer Biol (2019) 3:77–103. doi: 10.1146/annurev-cancerbio-030518-055653
104. Ranson T, Vosshenrich CAJ, Corcuff E, Richard O, Müller W, Di Santo JP. IL-15 Is an Essential Mediator of Peripheral NK-Cell Homeostasis. Blood (2003) 101:4887–93. doi: 10.1182/blood-2002-11-3392
105. Fujii R, Jochems C, Tritsch SR, Wong HC, Schlom J, Hodge JW. An IL-15 Superagonist/IL-15rα Fusion Complex Protects and Rescues NK Cell-Cytotoxic Function From TGF-β1-Mediated Immunosuppression. Cancer Immunol Immunother (2018) 67:675–89. doi: 10.1007/s00262-018-2121-4
106. Imamura M, Shook D, Kamiya T, Shimasaki N, Chai SMH, Coustan-Smith E, et al. Autonomous Growth and Increased Cytotoxicity of Natural Killer Cells Expressing Membrane-Bound Interleukin-15. Blood J Am Soc Hematol (2014) 124:1081–8. doi: 10.1182/blood-2014-02-556837
107. Kim PS, Kwilas AR, Xu W, Alter S, Jeng EK, Wong HC, et al. IL-15 Superagonist/IL-15rαsushi-Fc Fusion Complex (IL-15sa/IL-15rαsu-Fc; ALT-803) Markedly Enhances Specific Subpopulations of NK and Memory CD8+ T Cells, and Mediates Potent Anti-Tumor Activity Against Murine Breast and Colon Carcinomas. Oncotarget (2016) 7:16130. doi: 10.18632/oncotarget.7470
108. Woan KV, Kim H, Bjordahl R, Davis ZB, Gaidarova S, Goulding J, et al. Harnessing Features of Adaptive NK Cells to Generate iPSC-Derived NK Cells for Enhanced Immunotherapy. Cell Stem Cell (2021) 28:2062–75. doi: 10.1016/j.stem.2021.08.013
109. Long EO. Ready for Prime Time: NK Cell Priming by Dendritic Cells. Immunity (2007) 26:385–7. doi: 10.1016/j.immuni.2007.04.001
110. Foltz JA, Berrien-Elliott MM, Neal C, Foster M, McClain E, Schappe T, et al. Cytokine-Induced Memory-Like (ML) NK Cells Persist for> 2 Months Following Adoptive Transfer Into Leukemia Patients With a MHC-Compatible Hematopoietic Cell Transplant (HCT). Blood (2019) 134:1954. doi: 10.1182/blood-2019-126004
111. Bednarski JJ, Zimmerman C, Cashen AF, Desai S, Foster M, Schappe T, et al. Adoptively Transferred Donor-Derived Cytokine Induced Memory-Like NK Cells Persist and Induce Remission in Pediatric Patient With Relapsed Acute Myeloid Leukemia After Hematopoietic Cell Transplantation. Blood (2019) 134:3307. doi: 10.1182/blood-2019-126982
112. Romee R, Rosario M, Berrien-Elliott MM, Wagner JA, Jewell BA, Schappe T, et al. Cytokine-Induced Memory-Like Natural Killer Cells Exhibit Enhanced Responses Against Myeloid Leukemia. Sci Transl Med (2016) 8(357):357ra123. doi: 10.1126/scitranslmed.aaf2341
113. Uppendahl LD, Felices M, Bendzick L, Ryan C, Kodal B, Hinderlie P, et al. Cytokine-Induced Memory-Like Natural Killer Cells Have Enhanced Function, Proliferation, and In Vivo Expansion Against Ovarian Cancer Cells. Gynecol Oncol (2019) 153:149–57. doi: 10.1016/j.ygyno.2019.01.006
114. Gang M, Wong P, Berrien-Elliott MM, Fehniger TA. Memory-Like Natural Killer Cells for Cancer Immunotherapy. Semin Hematol Elsevier (2020) 57:185–93. doi: 10.1053/j.seminhematol.2020.11.003
115. Kantarjian H, Jabbour E, Topp MS. Blinatumomab for Acute Lymphoblastic Leukemia. N Engl J Med (2017) 376:e49. doi: 10.1056/NEJMc1704012
116. Kerbauy LN, Marin ND, Kaplan M, Banerjee PP, Berrien-Elliott MM, Becker-Hapak M, et al. Combining AFM13, a Bispecific CD30/CD16 Antibody, With Cytokine-Activated Blood and Cord Blood–Derived NK Cells Facilitates CAR-Like Responses Against CD30+ Malignancies. Clin Cancer Res (2021) 27:3744–56. doi: 10.1158/1078-0432.CCR-21-0164
117. Sarhan D, Brandt L, Felices M, Guldevall K, Lenvik T, Hinderlie P, et al. 161533 TriKE Stimulates NK-Cell Function to Overcome Myeloid-Derived Suppressor Cells in MDS. Blood Adv (2018) 2:1459–69. doi: 10.1182/bloodadvances.2017012369
118. Gleason MK, Ross JA, Warlick ED, Lund TC, Verneris MR, Wiernik A, et al. CD16xCD33 Bispecific Killer Cell Engager (BiKE) Activates NK Cells Against Primary MDS and MDSC CD33+ Targets. Blood J Am Soc Hematol (2014) 123:3016–26. doi: 10.1182/blood-2013-10-533398
119. Schmohl JU, Felices M, Taras E, Miller JS, Vallera DA. Enhanced ADCC and NK Cell Activation of an Anticarcinoma Bispecific Antibody by Genetic Insertion of a Modified IL-15 Cross-Linker. Mol Ther (2016) 24:1312–22. doi: 10.1038/mt.2016.88
120. Schmohl JU, Felices M, Oh F, Lenvik AJ, Lebeau AM, Panyam J, et al. Engineering of Anti-CD133 Trispecific Molecule Capable of Inducing NK Expansion and Driving Antibody-Dependent Cell-Mediated Cytotoxicity. Cancer Res Treat Off J Korean Cancer Assoc (2017) 49:1140. doi: 10.4143/crt.2016.491
121. Reusing SB, Vallera DA, Manser AR, Vatrin T, Bhatia S, Felices M, et al. CD16xCD33 Bispecific Killer Cell Engager (BiKE) as Potential Immunotherapeutic in Pediatric Patients With AML and Biphenotypic ALL. Cancer Immunol Immunother (2021) 70:3701–8. doi: 10.1007/s00262-021-03008-0
122. Arvindam US, van Hauten P, Hallstrom C, Vallera DA, Dolstra H, Miller JS, et al. CD16-IL15-CLEC12A Trispecific Killer Engager (TriKE) Drives NK Cell Expansion, Activation, and Antigen Specific Killing of Cancer Stem Cells in Acute Myeloid Leukemia. Blood (2018) 132:1454. doi: 10.1182/blood-2018-99-117150
123. Yano T, Ohira M, Nakano R, Tanaka Y, Ohdan H. Hepatectomy Leads to Loss of TRAIL-Expressing Liver NK Cells via Downregulation of the CXCL9-CXCR3 Axis in Mice. PloS One (2017) 12:e0186997. doi: 10.1371/journal.pone.0186997
124. El-Shemi AG, Ashshi AM, Na Y, Li Y, Basalamah M, Al-Allaf FA, et al. Combined Therapy With Oncolytic Adenoviruses Encoding TRAIL and IL-12 Genes Markedly Suppressed Human Hepatocellular Carcinoma Both In Vitro and in an Orthotopic Transplanted Mouse Model. J Exp Clin Cancer Res (2016) 35:1–16. doi: 10.1186/s13046-016-0353-8
125. Yilmaz A, Cui H, Caligiuri MA, Yu J. Chimeric Antigen Receptor-Engineered Natural Killer Cells for Cancer Immunotherapy. J Hematol Oncol (2020) 13:1–22. doi: 10.1186/s13045-020-00998-9
126. Kamiya T, Chang Y-H, Campana D. Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma. Cancer Immunol Res (2016) 4:574–81. doi: 10.1158/2326-6066.CIR-15-0229
127. Ushijima H, Monzaki R, Funakoshi M. Analysis of Differentially Expressed Genes Responsible for the Suppressive Effect of Anisomycin on Cell Proliferation of DLD-1 Cells. Biochem Biophys Rep (2021) 27:101038. doi: 10.1016/j.bbrep.2021.101038
128. Kim M, Lee S-J, Shin S, Park K-S, Park SY, Lee CH. Novel Natural Killer Cell-Mediated Cancer Immunotherapeutic Activity of Anisomycin Against Hepatocellular Carcinoma Cells. Sci Rep (2018) 8:1–12. doi: 10.1038/s41598-018-29048-8
129. Arai J, Goto K, Tanoue Y, Ito S, Muroyama R, Matsubara Y, et al. Enzymatic Inhibition of MICA Sheddase ADAM17 by Lomofungin in Hepatocellular Carcinoma Cells. Int J Cancer (2018) 143:2575–83. doi: 10.1002/ijc.31615
130. Arai J, Goto K, Otoyama Y, Nakajima Y, Sugiura I, Kajiwara A, et al. Leukotriene Receptor Antagonists Enhance HCC Treatment Efficacy by Inhibiting ADAMs and Suppressing MICA Shedding. Cancer Immunol Immunother (2021) 70:203–13. doi: 10.1007/s00262-020-02660-2
131. Shin S, Kim M, Lee S-J, Park K-S, Lee CH. Trichostatin A Sensitizes Hepatocellular Carcinoma Cells to Enhanced NK Cell-Mediated Killing by Regulating Immune-Related Genes. Cancer Genomics Proteomics (2017) 14:349–62. doi: 10.21873/cgp.20045
132. Shu G, Yang T, Wang C, Su H, Xiang M. Gastrodin Stimulates Anticancer Immune Response and Represses Transplanted H22 Hepatic Ascitic Tumor Cell Growth: Involvement of NF-κb Signaling Activation in CD4+ T Cells. Toxicol Appl Pharmacol (2013) 269:270–9. doi: 10.1016/j.taap.2013.02.019
133. Wan L, Zhang D, Zhang J, Ren L. Anti-Hepatocarcinoma Activity of TT-1, an Analog of Melittin, Combined With Interferon-α via Promoting the Interaction of NKG2D and MICA. J Zhejiang Univ B (2017) 18:522–31. doi: 10.1631/jzus.B1600369
134. Yavari M, Salesi Z, Derakhti A, Azimzadeh S, Varpaei HA, Esmaeili H, et al. Melittin and Breast Cancer: A Brief Review of the Evidence. J Nurs Patient Saf (2020) 20:1–7. doi: 10.47755/2766-9653.1000101
135. Xu T, Cui T, Peng L, Kong S, Zou J, Tian X. The Anti−Hepatocellular Carcinoma Activity of Mel−P15 is Mediated by Natural Killer Cells. Oncol Lett (2017) 14:6901–6. doi: 10.3892/ol.2017.7018
136. Trojan J, Waidmann O. Role of Regorafenib as Second-Line Therapy and Landscape of Investigational Treatment Options in Advanced Hepatocellular Carcinoma. J Hepatocell Carcinoma (2016) 3:31. doi: 10.2147/JHC.S112537
137. Nowakowska P, Romanski A, Miller N, Odendahl M, Bonig H, Zhang C, et al. Clinical Grade Manufacturing of Genetically Modified, CAR-Expressing NK-92 Cells for the Treatment of ErbB2-Positive Malignancies. Cancer Immunol Immunother (2018) 67:25–38. doi: 10.1007/s00262-017-2055-2
138. Mizukoshi E, Kaneko S. Immune Cell Therapy for Hepatocellular Carcinoma. J Hematol Oncol (2019) 12:1–11. doi: 10.1186/s13045-019-0742-5
139. Wang Y, Luo F, Yang J, Zhao C, Chu Y. New Chimeric Antigen Receptor Design for Solid Tumors. Front Immunol (2017) 8:1934. doi: 10.3389/fimmu.2017.01934
140. Sadelain M, Brentjens R, Rivière I. The Basic Principles of Chimeric Antigen Receptor Design. Cancer Discov (2013) 3:388–98. doi: 10.1158/2159-8290.CD-12-0548
141. Xu Y, Liu Q, Zhong M, Wang Z, Chen Z, Zhang Y, et al. 2B4 Costimulatory Domain Enhancing Cytotoxic Ability of Anti-CD5 Chimeric Antigen Receptor Engineered Natural Killer Cells Against T Cell Malignancies. J Hematol Oncol (2019) 12:1–13. doi: 10.1186/s13045-019-0732-7
142. Li Y, Hermanson DL, Moriarity BS, Kaufman DS. Human iPSC-Derived Natural Killer Cells Engineered With Chimeric Antigen Receptors Enhance Anti-Tumor Activity. Cell Stem Cell (2018) 23:181–92. doi: 10.1016/j.stem.2018.06.002
143. Oei VYS, Siernicka M, Graczyk-Jarzynka A, Hoel HJ, Yang W, Palacios D, et al. Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors. Cancer Immunol Res (2018) 6:467–80. doi: 10.1158/2326-6066.CIR-17-0207
Keywords: HCC, NK cells, innate immune landscape, tumor immune microenvironment, HBV induced HCC
Citation: Sajid M, Liu L and Sun C (2022) The Dynamic Role of NK Cells in Liver Cancers: Role in HCC and HBV Associated HCC and Its Therapeutic Implications. Front. Immunol. 13:887186. doi: 10.3389/fimmu.2022.887186
Received: 01 March 2022; Accepted: 12 April 2022;
Published: 20 May 2022.
Edited by:
Vikas Duhan, The University of Queensland, AustraliaReviewed by:
Vishal Khairnar, Dana–Farber Cancer Institute, United StatesFabio Guolo, San Martino Hospital (IRCCS), Italy
Copyright © 2022 Sajid, Liu and Sun. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Lianxin Liu, liulx@ustc.edu.cn; Cheng Sun, charless@ustc.edu.cn