Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients

Cai, Liang; Zhang, Zheng; Zhou, Lin; Wang, Haiyan; Fu, Junliang; Zhang, Shuye; Shi, Min; Zhang, Hui; Yang, Yongping; Wu, Hao; Tien, Po; Wang, Fusheng

doi:10.1016/j.clim.2008.08.012

Cited by 260 publications

(257 citation statements)

References 29 publications

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“…A decreased expression of NKG2D 11 and of perforin 3 has already been described in HCC. Conversely, low expression of NKG2A is in contrast to previous data generated from patients with advanced disease, 3 showing similar levels of expression compared to healthy controls. The decreased expression of NKG2A observed in the present study might be a consequence of downregulation upon interaction with MHC ligand in the context of an exhausted NK-cell phenotype, consistent with the decreased expression of CD3z, perforin and NKG2D.…”

Section: Discussioncontrasting

confidence: 86%

“…Decreased expression of inhibitory receptor NKG2A and of molecules linked to effector function (CD3z, perforin) was present in peripheral blood NK-cells from HCC patients. A prevalent CD56 BR phenotype, as previously reported, 3 and decreased expression of activating receptor NKG2D was also observed in HCC patients, even though the lack of a significant difference compared to cirrhotic patients does not rule out the role of HCV infection as responsible for this phenotype.…”

Section: Discussionsupporting

confidence: 66%

“…2 Evidence in HCC showed decreased NK subset in peripheral blood and in tumor compared to non-tumor liver tissue. 3,4 In addition, functional defects such as impaired cytokine production and killing [3][4][5][6] were observed, mainly in NK-cells from patients with advanced stage HCC, 4 and were shown to represent a negative prognostic factor after hepatectomy. 5 Conversely, accumulation of functional NK-cells in HCC tissues has been shown to predict improved survival of patients.…”

Section: Introductionmentioning

confidence: 99%

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Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments

et al. 2016

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(controls) were phenotypically characterized. Unsupervised clustering based on the frequency of cells expressing different phenotypic NK-cell markers segregated HCC patients into different cohorts that were compared for outcome. NK-cell cytokine production and cytotoxicity were compared between cohorts with different overall survival (OS) and time to disease recurrence (TTR). By multivariate analysis, age, Child-Pugh class and NK-cell phenotypic clustering could independently identify patients with significantly different OS. NK-cells from patients with better outcome expressed higher levels of cytotoxic granules and CD3z and lower levels of natural cytotoxic receptors (NCRs) that were co-expressed with the inhibitory receptor NKG2A known to negatively regulate NCR function. Cytotoxic function and IFNg production were significantly lower in the cohort of patients with worse outcome compared to controls (p < 0.05). Our results show a role for NK-cells in the control of HCC progression and survival providing the basis for the development of immunotherapeutic strategies to potentiate NK-cell response.

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Section: Discussioncontrasting

confidence: 86%

Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

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Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments

et al. 2016

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“…Moreover, the ratio of CD56 bright and CD56 dim NK cells was dramatically increased in HCC patients because CD56 bright CD16 2 NK cells were expanded and CD56 dim CD16 1 NK cells were reduced. 59 The absolute counts of CD56 bright and CD56 dim NK cells were found reduced in peripheral blood from 20 Egyptian patients with HCC compared to 152 healthy control subjects. 60 Liver NK cells in HCC Due to the limited supply of fresh liver tissue samples from patients, the majority of NK cells that have been studied were derived from circulating NK cells in HCC.…”

Section: Abnormal Nk Cells In Hcc Patientsmentioning

confidence: 91%

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

et al. 2014

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Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. There is a significant correlation between chronic hepatitis B virus (HBV) infection and hepatocarcinogenesis. As the first line of host defense against viral infections and tumors, natural killer (NK) cells express a large number of immune recognition receptors (NK receptors (NKRs)) to recognize ligands on hepatocytes, liver sinusoidal endothelial cells, stellate cells and Kupffer cells, which maintain the balance between immune response and immune tolerance of NK cells. Unfortunately, the percentage and absolute number of liver NK cells decrease significantly during the development and progression of HCC. The abnormal expression of NK cell receptors and dysfunction of liver NK cells contribute to the progression of chronic HBV infection and HCC and are significantly associated with poor prognosis for liver cancer. In this review, we focus on the role of NK cell receptors in anti-tumor immune responses in HCC, particularly HBV-related HCC. We discuss specifically how tumor cells evade attack from NK cells and how emerging understanding of NKRs may aid the development of novel treatments for HCC. Novel mono-and combination therapeutic strategies that target the NK cell receptor-ligand system may potentially lead to successful and effective immunotherapy in HCC. Keywords: activating receptor; hepatocellular carcinoma; inhibitory receptor; natural killer cell; natural killer receptor INTRODUCTION Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. 1 Common clinical risk factors for HCC include hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, heavy alcohol intake, steatohepatitis and diabetes. 2 Approximately 50% of HCC cases worldwide can be attributed to chronic HBV infection (CHB) and almost 75% of HCC cases occur in developing countries where HBV is endemic. 3,4 According to statistics, older male patients who are infected with HBV genotype C or co-infected with HCV, have high levels of viral load and have been exposed to the aflatoxin, or older male patients who have a family history of HCC tend to have a high risk of developing HCC. [5][6][7] Accumulating clinical and epidemiological evidence shows a significant correlation between chronic HBV infection and hepatocarcinogenesis. However, the underlying mechanisms

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“…Cell cytotoxicity was determined by dual-color flow cytometry using the HCC cell lines Hep3B or HepG2 as target cells, whereas PBMCs, NK cells, or NK cell-depleted PBMCs as effector cells (19).…”

Section: Cell Cytotoxicity Assaymentioning

confidence: 99%

Granulin–Epithelin Precursor Renders Hepatocellular Carcinoma Cells Resistant to Natural Killer Cytotoxicity

Cheung

Yip

Wong

et al. 2014

Cancer Immunology Research

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Immunoevasion is an emerging hallmark of cancer. Impairment of natural killer (NK) cytotoxicity is a mechanism to evade host immunosurveillance. Granulin-epithelin precursor (GEP) is a hepatic oncofetal protein regulating growth, invasion, and chemoresistance in hepatocellular carcinoma (HCC). We examined the role of GEP in conferring HCC cells the ability to evade NK cytotoxicity. In HCC cell lines, GEP overexpression reduced, whereas GEP suppression enhanced sensitivity to NK cytotoxicity. GEP downregulated surface expression of MHC class I chain-related molecule A (MICA), ligand for NK stimulatory receptor NK group 2 member D (NKG2D), and upregulated human leukocyte antigen-E (HLA-E), ligand for NK inhibitory receptor CD94/NKG2A. Functionally, GEP augmented production of soluble MICA, which suppressed NK activation. Matrix metalloproteinase (MMP)2 and MMP9 activity was involved partly in the GEP-regulated MICA shedding from HCC cells. In primary HCCs (n ¼ 80), elevated GEP (P < 0.001), MICA (P < 0.001), and HLA-E (P ¼ 0.089) expression was observed when compared with those in nontumor (n ¼ 80) and normal livers (n ¼ 10). Serum GEP (P ¼ 0.010) and MICA (P < 0.001) levels were higher in patients with HCC (n ¼ 80) than in healthy individuals (n ¼ 30). High serum GEP and/or MICA levels were associated with poor recurrence-free survival (log-rank test, P ¼ 0.042). Importantly, GEP blockade by mAbs sensitized HCC cells to NK cytotoxicity through MICA. In summary, GEP rendered HCC cells resistant to NK cytotoxicity by modulating MICA expression, which could be reversed by GEP blockade using antibody. Serum GEP and MICA levels are prognostic factors and can be used to stratify patients for targeted therapy.

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Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients

Cited by 260 publications

References 29 publications

Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments

Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

Granulin–Epithelin Precursor Renders Hepatocellular Carcinoma Cells Resistant to Natural Killer Cytotoxicity

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