scholarly journals NLRP3 Deficiency in Hepatocellular Carcinoma Enhances Surveillance of NK-92 through a Modulation of MICA/B

2021 ◽  
Vol 22 (17) ◽  
pp. 9285
Author(s):  
Hwan Hee Lee ◽  
Dongoh Kim ◽  
Joohee Jung ◽  
Hyojeung Kang ◽  
Hyosun Cho
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nk Cells ◽  
Nlrp3 Inflammasome ◽  
Nk Cell ◽  
Tumor Development ◽  
Low Frequency ◽  
Cancer Surveillance ◽  
Mice Model ◽  
Liver Cancers ◽  
Hcc Cells

Human hepatocellular carcinoma (HCC) is the most common and even worse at prognosis. The patients with HCC which accompanied by other diseases, such as cirrhosis, can be limited in various treatments, such as chemotherapy, not HCC patients without other diseases. NLRP3 inflammasome plays an important role in the innate immune response, but emerging evidence has indicated that the NLRP3 inflammasome is implicated in all stages of cancer development. Various cells express NLRP3 protein through the autocrine or paracrine signaling in their environment, but NK cells do not. The expanding evidence shows that patients who suffer from liver cancers have a low frequency of natural killer (NK) cells, and the function of these cells is also impaired. Thus, we examined how the expression of NLRP3 in HCC cells affects cancer surveillance by NK cells in a state of a co-culture of both cells. When the expression of NLRP3 in HCC cells was ablated, MICA/B on the surface of HCC cells was upregulated through the lowered expression of matrix metalloproteinase. The expression of MICA on the surface of HCC cells interacted with the NKG2D receptor on NK-92 cells, which led to NK cytotoxicity. Furthermore, in a xenograft mice model, NLRP3 KO HCC cells delayed tumor development and metastasis as well as increased the sensitivity to NK cell cytotoxicity. Taken together, NLRP3 KO in HCC could enhance NK immunosurveillance through an interaction of NKG2D-MICA.

scholarly journals An Anti-MICA/B Antibody and IL-15 Rescue Altered NKG2D-Dependent NK Cell Responses in Hepatocellular Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3583
Author(s):  
Stefania Mantovani ◽  
Stefania Varchetta ◽  
Dalila Mele ◽  
Matteo Donadon ◽  
Guido Torzilli ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Protein A ◽  
Ligand Interaction ◽  
Cell Responses ◽  
Hcc Cells

Natural killer (NK) cells play a pivotal role in cancer immune surveillance, and activating the receptor/ligand interaction may contribute to control the development and evolution of hepatocellular carcinoma (HCC). We investigated the role of the natural killer group 2 member D (NKG2D) activating receptor and its ligand, the major histocompatibility complex class I chain-related protein A and B (MICA/B) in patients with cirrhosis and HCC subjected to surgical resection, patients with cirrhosis and no HCC, and healthy donors (HD). The NKG2D-mediated function was determined in peripheral blood (PB), in tumor-infiltrating lymphocytes (NK-TIL), and in matched surrounding liver tissue (NK-LIL). A group of patients treated with sorafenib because of clinically advanced HCC was also studied. A humanized anti-MICA/B monoclonal antibody (mAb) was used in in vitro experiments to examine NK cell-mediated antibody-dependent cellular cytotoxicity. Serum concentrations of soluble MICA/B were evaluated by ELISA. IL-15 stimulation increased NKG2D-dependent activity which, however, remained dysfunctional in PB NK cells from HCC patients, in line with the reduced NKG2D expression on NK cells. NK-TIL showed a lower degranulation ability than NK-LIL, which was restored by IL-15 stimulation. Moreover, in vitro IL-15 stimulation enhanced degranulation and interferon-γ production by PB NK from patients at month one of treatment with sorafenib. Anti-MICA/B mAb associated with IL-15 was able to induce PB NK cytotoxicity for primary HCC cells in HD and patients with HCC, who also showed NK-TIL degranulation for autologous primary HCC cells. Our findings highlight the key role of the NKG2D-MICA/B axis in the regulation of NK cell responses in HCC and provide evidence in support of a potentially important role of anti-MICA/B mAb and IL-15 stimulation in HCC immunotherapy.

scholarly journals Cytotoxicity of Human Hepatic Intrasinusoidal CD56bright Natural Killer Cells against Hepatocellular Carcinoma Cells

2019 ◽  
Vol 20 (7) ◽  
pp. 1564 ◽  
Author(s):  
Shin Hwang ◽  
Jaeseok Han ◽  
Ji-Seok Baek ◽  
Eunyoung Tak ◽  
Gi-Won Song ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nk Cells ◽  
Natural Killer ◽  
Fas Ligand ◽  
Nk Cell ◽  
Carcinoma Cells ◽  
Huh7 Cells ◽  
Ifn Γ ◽  
And Function ◽  
Hcc Cells

Hepatic intrasinusoidal (HI) natural killer (NK) cells from liver perfusate have unique features that are similar to those of liver-resident NK cells. Previously, we have reported that HI CD56bright NK cells effectively degranulate against SNU398 hepatocellular carcinoma (HCC) cells. Thus, the aim of this study was to further investigate the phenotype and function of HI NK cells. We found that HI CD56bright NK cells degranulated much less to Huh7 cells. HI CD56bright NK cells expressed NKG2D, NKp46, TNF-related apoptosis-inducing ligand (TRAIL), and FAS ligand (FASL) at higher levels than CD56dim cells. SNU398 cells expressed more NKG2D ligands and FAS and less PD-L1 than Huh7 cells. Blockade of NKG2D, TRAIL, and FASL significantly reduced the cytotoxicity of HI NK cells against SNU398 cells, but blockade of PD-L1 did not lead to any significant change. However, HI NK cells produced IFN-γ well in response to Huh7 cells. In conclusion, the cytotoxicity of HI CD56bright NK cells was attributed to the expression of NKG2D, TRAIL, and FASL. The results suggest the possible use of HI NK cells for cancer immunotherapy and prescreening of HCC cells to help identify the most effective NK cell therapy recipients.

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

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Pingyi Liu ◽  
Lingling Chen ◽  
Haiyan Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Disease ◽  
Nk Cells ◽  
Nk Cell ◽  
Hepatitis Virus ◽  
Critical Role ◽  
Immune Defense ◽  
Cell Phenotype ◽  
Functional Changes ◽  
Liver Cancers

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.

scholarly journals The Advances and Challenges of NK Cell-Based Cancer Immunotherapy

2021 ◽  
Vol 28 (2) ◽  
pp. 1077-1093
Author(s):  
Synat Kang ◽  
Xuefeng Gao ◽  
Li Zhang ◽  
Erna Yang ◽  
Yonghui Li ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Nk Cell ◽  
Tumor Development ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Clinical Applications ◽  
Therapeutic Approaches ◽  
Leukocyte Antigens ◽  
Recognition Specificity

Natural killer (NK) cells can be widely applied for cancer immunotherapy due to their ability to lyse tumor targets without prior sensitization or human leukocyte antigens-matching. Several NK-based therapeutic approaches have been attempted in clinical practice, but their efficacy is not sufficient to suppress tumor development mainly because of lacking specificity. To this end, the engineering of NK cells with T cell receptor along with CD3 subunits (TCR-NK) has been developed to increase the reactivity and recognition specificity of NK cells toward tumor cells. Here, we review recent advances in redirecting NK cells for cancer immunotherapy and discuss the major challenges and future explorations for their clinical applications.

scholarly journals Cancer exosomes and natural killer cells dysfunction: biological roles, clinical significance and implications for immunotherapy

2022 ◽  
Vol 21 (1) ◽  
Author(s):  
Reza Hosseini ◽  
Hamzeh Sarvnaz ◽  
Maedeh Arabpour ◽  
Samira Molaei Ramshe ◽  
Leila Asef-Kabiri ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Clinical Significance ◽  
Surveillance System ◽  
Cancer Biology ◽  
Nk Cell ◽  
Ex Vivo ◽  
Immune Surveillance ◽  
Tumor Development ◽  
Cell Responses

AbstractTumor-derived exosomes (TDEs) play pivotal roles in several aspects of cancer biology. It is now evident that TDEs also favor tumor growth by negatively affecting anti-tumor immunity. As important sentinels of immune surveillance system, natural killer (NK) cells can recognize malignant cells very early and counteract the tumor development and metastasis without a need for additional activation. Based on this rationale, adoptive transfer of ex vivo expanded NK cells/NK cell lines, such as NK-92 cells, has attracted great attention and is widely studied as a promising immunotherapy for cancer treatment. However, by exploiting various strategies, including secretion of exosomes, cancer cells are able to subvert NK cell responses. This paper reviews the roles of TDEs in cancer-induced NK cells impairments with mechanistic insights. The clinical significance and potential approaches to nullify the effects of TDEs on NK cells in cancer immunotherapy are also discussed.

scholarly journals Inhibition of Enhancer of zeste homolog 2 (EZH2) induces natural killer cell-mediated eradication of hepatocellular carcinoma cells

2018 ◽  
Vol 115 (15) ◽  
pp. E3509-E3518 ◽  
Author(s):  
Suresh Bugide ◽  
Michael R. Green ◽  
Narendra Wajapeyee
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Down Regulation ◽  
Nkg2d Ligands ◽  
Enhancer Of Zeste

Natural killer (NK) cell-mediated tumor cell eradication could inhibit tumor initiation and progression. However, the factors that regulate NK cell-mediated cancer cell eradication remain unclear. We determined that hepatocellular carcinoma (HCC) cells exhibit transcriptional down-regulation of NK group 2D (NKG2D) ligands and are largely resistant to NK cell-mediated eradication. Because the down-regulation of NKG2D ligands occurred at the transcriptional level, we tested 32 chemical inhibitors of epigenetic regulators for their ability to re-express NKG2D ligands and enhance HCC cell eradication by NK cells and found that Enhancer of zeste homolog 2 (EZH2) was a transcriptional repressor of NKG2D ligands. The inhibition of EZH2 by small-molecule inhibitors or genetic means enhanced HCC cell eradication by NK cells in a NKG2D ligand-dependent manner. Collectively, these results demonstrate that EZH2 inhibition enhances HCC eradication by NK cells and that EZH2 functions, in part, as an oncogene by inhibiting immune response.

scholarly journals Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 926 ◽  
Author(s):  
Stefania Mantovani ◽  
Barbara Oliviero ◽  
Stefania Varchetta ◽  
Dalila Mele ◽  
Mario U. Mondelli
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Escape ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Current Status ◽  
Tumor Immune Escape

Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri- and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects.

scholarly journals Upregulation of histamine receptor H1 promotes tumor progression and contributes to poor prognosis in hepatocellular carcinoma

Oncogene ◽  
2019 ◽  
Vol 39 (8) ◽  
pp. 1724-1738 ◽  
Author(s):  
Jing Zhao ◽  
Yiran Hou ◽  
Chun Yin ◽  
Jing Hu ◽  
Tian Gao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Progression ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Histamine Receptor ◽  
Matrix Metalloproteinase 2 ◽  
Mice Model ◽  
Hcc Cells

AbstractH1 histamine receptor (H1HR) belongs to the family of rhodopsin-like G-protein-coupled receptors. Recent studies have shown that H1HR expression is increased in several types of cancer. However, its functional roles in tumor progression remain largely unknown, especially in hepatocellular carcinoma (HCC). We found that H1HR is frequently unregulated in HCC, which is significantly associated with both recurrence-free survival and overall survival in HCC patients. Functional experiments revealed that H1HR promoted both the growth and metastasis of HCC cells by inducing cell cycle progression, formation of lamellipodia, production of matrix metalloproteinase 2, and suppression of cell apoptosis. Activation of cyclic adenosine monophosphate-dependent protein kinase A was found to be involved in H1HR-mediated HCC cell growth and metastasis. In addition, we found that overexpression of H1HR was mainly due to the downregulation of miR-940 in HCC cells. Moreover, the H1HR inhibitor terfenadine significantly suppressed tumor growth and metastasis in an HCC xenograft nude mice model. Our findings demonstrate that H1HR plays a critical role in the growth and metastasis of HCC cells, which provides experimental evidence supporting H1HR as a potential drug target for the treatment of HCC.

scholarly journals Correlation between p53 expression and hepatocellular carcinoma differentiation grade

2020 ◽  
Vol 55 (1) ◽  
pp. 28-31
Author(s):  
B. K. Issamatov ◽  
E. A. Yenin ◽  
U. Sh. Medeubekov ◽  
B. B. Baymakhanov
Keyword(s):  
Hepatocellular Carcinoma ◽  
P53 Gene ◽  
Expression Level ◽  
Simultaneous Increase ◽  
Malignant Neoplasms ◽  
P53 Expression ◽  
Liver Cancers ◽  
Well Differentiated ◽  
High Level ◽  
Hcc Cells

Relevance: Hepatocellular carcinoma (HCC) is one of the world’s most common liver cancers and fatal malignant neoplasms. According to GLOBOCAN 2018, liver cancer ranks sixth in incidence (842,000 new cases) and fourth in mortality (782,000 deaths) globally. In Kazakhstan, there is an increase in HCC incidence from 879 cases in 2016 up to 984 cases in 2017, which amounted to 5.5 cases per 100 000 population. In 2017, the five-year survival rate was 23.7%. The mutations in the p53 gene that encodes the p53 protein are most frequent in HCC (35.2%). A high level of nuclear expression of p53 and a decrease in apoptosis of tumor cells with a simultaneous increase in their proliferative activity, noted in HCC cells, are important for the prognosis of the disease. There is a correlation between poor prognosis, a decreased survival of patients with HCC, and high expression of the p53 oncoprotein in HCC. U. Nzeako et al. have revealed a strong correlation of HCC histological differentiation with the patient survival rate. Therefore, a study of the correlation between p53 expression and HCC differentiation grade is very relevant. The purpose of this study was to analyze the correlation between p53 expression and HCC differentiation grade. Results: p53 was overexpressed in 18% of HCC cases; the expression was high in 62% and low in 20% of HCC cases. In well-differentiated HCC (G1), the p53-immunopositive nuclei expression was low in 10 cases and high in 2 cases. In moderately differentiated HCC (G2), p53 was highly expressed in 21 cases and overexpressed in 2 cases. In low-differentiated HCC (G3), p53 was overexpressed in 7 cases and highly expressed in 8 cases of HCC. The analysis of the correlation between p53 expression and HCC differentiation grade by Spearman showed a high correlation (r=0.79, p<0.01), evidencing a direct dependence of p53 expression level on HCC gradation. Conclusion: HCC differentiation grade highly correlates with p53 expression level in immunopositive nuclei of HCC cells. The obtained data evidences a dependence between p53 expression level and HCC gradation.

scholarly journals Correlation between p53 expression and hepatocellular carcinoma differentiation grade

2020 ◽  
Vol 55 (1) ◽  
pp. 25-27
Author(s):  
B. K. ISSAMATOV ◽  
E. A. YENIN ◽  
U. Sh. MEDEUBEKOV ◽  
B. B. BAYMAKHANOV
Keyword(s):  
Hepatocellular Carcinoma ◽  
Survival Rate ◽  
P53 Protein ◽  
P53 Gene ◽  
Expression Level ◽  
Simultaneous Increase ◽  
Malignant Neoplasms ◽  
P53 Expression ◽  
Liver Cancers ◽  
Hcc Cells

Relevance: Hepatocellular carcinoma (HCC) is one of the world’s most common liver cancers and fatal malignant neoplasms. According to GLOBOCAN 2018, liver cancer ranks sixth in incidence (842,000 new cases) and fourth in mortality (782,000 deaths) globally. In Kazakhstan, there is an increase in HCC incidence from 879 cases in 2016 up to 984 cases in 2017, which amounted to 5.5 cases per 100 000 population. In 2017, the five-year survival rate was 23.7%. The mutations in the p53 gene that encodes the p53 protein are most frequent in HCC (35.2%). A high level of nuclear expression of p53 and a decrease in apoptosis of tumor cells with a simultaneous increase in their proliferative activity, noted in HCC cells, are important for the prognosis of the disease. There is a correlation between poor prognosis, a decreased survival of patients with HCC, and high expression of the p53 oncoprotein in HCC. U. Nzeako et al. have revealed a strong correlation of HCC histological differentiation with the patient survival rate. Therefore, a study of the correlation between p53 expression and HCC differentiation grade is very relevant. The purpose of this study was to analyze the correlation between p53 expression and HCC differentiation grade. Results: p53 was overexpressed in 18% of HCC cases; the expression was high in 62% and low in 20% of HCC cases. In well-differentiated HCC (G1), the p53-immunopositive nuclei expression was low in 10 cases and high in 2 cases. In moderately differentiated HCC (G2), p53 was highly expressed in 21 cases and overexpressed in 2 cases. In poorly-differentiated HCC (G3), p53 was overexpressed in 7 cases and highly expressed in 8 cases of HCC. The analysis of the correlation between p53 expression and HCC differentiation grade by Spearman showed a high correlation (r=0.79, p<0.01), evidencing a direct dependence of p53 expression level on HCC gradation. Conclusion: HCC differentiation grade highly correlates with p53 expression level in immunopositive nuclei of HCC cells. The obtained data evidences a dependence between p53 expression level and HCC gradation.

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