Natural Killer Cell Dysfunction in Hepatocellular Carcinoma: Pathogenesis and Clinical Implications

Sung, Pil Soo; Jang, Jeong Won

doi:10.3390/ijms19113648

Cited by 45 publications

(45 citation statements)

References 150 publications

(222 reference statements)

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“…Moreover, both CD56 dim and CD56 bright NK cells in patients with end-stage HCC exhibited anergic effector functions in the peripheral blood and at the tumor site[ 103 ]. Specifically, reduced NK cell cytotoxic activity ( i.e ., lower production of granzymes and cytotoxic perforin) and lower secretion of cytokines ( i.e ., TNF-a and IFN-γ) associated with the progression and invasion of HCC were reported[ 111 , 112 ]. Various mechanisms are involved in the functional impairment of NK cells in advanced HCC[ 113 ].…”

Section: Hccmentioning

confidence: 99%

“…Numerus strategies employed by HCC to evade NK cell immunosurveillance in later stages of the disease are used for HCC treatment[ 112 , 113 ]. Molecular target drugs such as sorafenib, a multikinase inhibitor, and bortezomib, a proteasome inhibitor, trigger hepatic NK cell antitumor responses, resulting in higher cytotoxicity and IFN-γ production[ 126 ].…”

Section: Hccmentioning

confidence: 99%

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Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells

Polidoro¹,

Mikulak²,

Cazzetta³

et al. 2020

WJG

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In the last years, several studies have been focused on elucidate the role of tumor microenvironment (TME) in cancer development and progression. Within TME, cells from adaptive and innate immune system are one of the main abundant components. The dynamic interactions between immune and cancer cells lead to the activation of complex molecular mechanisms that sustain tumor growth. This important cross-talk has been elucidate for several kind of tumors and occurs also in patients with liver cancer, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Liver is well-known to be an important immunological organ with unique microenvironment. Here, in normal conditions, the rich immune-infiltrating cells cooperate with non-parenchymal cells, such as liver sinusoidal endothelial cells and Kupffer cells, favoring self-tolerance against gut antigens. The presence of underling liver immunosuppressive microenvironment highlights the importance to dissect the interaction between HCC and iCCA cells with immune infiltrating cells, in order to understand how this cross-talk promotes tumor growth. Deeper attention is, in fact, focused on immune-based therapy for these tumors, as promising approach to counteract the intrinsic anti-tumor activity of this microenvironment. In this review, we will examine the key pathways underlying TME cell-cell communications, with deeper focus on the role of natural killer cells in primary liver tumors, such as HCC and iCCA, as new opportunities for immune-based therapeutic strategies.

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Section: Hccmentioning

confidence: 99%

Section: Hccmentioning

confidence: 99%

Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells

Polidoro¹,

Mikulak²,

Cazzetta³

et al. 2020

WJG

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show abstract

“…The causes of dysfunctional NK cells can be broadly divided into two main categories: (1) quantitative de iciencies with low numbers or absent NK cells and (2) qualitative de iciencies with abnormal function of NK cells. The etiological causes and the associations of quantitative as well as qualitative NK cell de iciencies are shown in tables 2 and 3 [31,[34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52].…”

Section: Nk Cell Function and Dysfunctionmentioning

confidence: 99%

Natural killer cells in patients with hematologic malignancies, solid tumors and in recipients of hematopoietic stem cell transplantation

Ka¹,

Al-Jasser²,

Wk³

2019

J Stem Cell Ther Transplant

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“…6 Natural killer (NK) cells are essential lymphocytes that can kill virus-infected and cancer cells. [7][8][9] NK cells perform crucial functions during early HCC development. NK cells are defined as CD3 − CD56 + cells in humans and as CD3 − NK1.1 + or CD3 − NKp46 + cells in mice.…”

Section: Introductionmentioning

confidence: 99%

EpCAM-high liver cancer stem cells resist natural killer cell–mediated cytotoxicity by upregulating CEACAM1

Park

Sung

Kim

et al. 2020

J Immunother Cancer

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BackgroundNatural killer (NK) cells can recognize and kill cancer cells directly, but their activity can be attenuated by various inhibitory molecules expressed on the surface. The expression of epithelial cell adhesion molecule (EpCAM), a potential marker for cancer stem cells (CSCs), is known to be strongly associated with poor clinical outcomes in hepatocellular carcinoma (HCC). NK cells targeting CSCs may be a promising strategy for anti-tumor therapy, but little is known about how they respond to EpCAMhighCSCs in HCC.MethodsEpCAM expression was assessed by immunohistochemistry in 280 human HCC tissues obtained from curative surgery. To investigate the functional activity of NK cells against liver CSCs, EpCAMhighand EpCAMlowHuh-7 cells were sorted by flow cytometry. The functional role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is related to NK cells, was determined by in vitro co-culture of NK cells and hepatoma cells using Hepa1–6 mouse hepatoma cells, as well as in vivo experiments using C57/BL6 mice.ResultsThe frequency of recurrence after curative surgery was higher in patients with positive EpCAM expression than in those with negative EpCAM expression. In subsequent analysis based on the anatomical location of EpCAM expression, patients with peritumoral EpCAM expression showed worse prognosis than those with pantumoral EpCAM expression. Co-culture experiments demonstrated that CEACAM1 was upregulated on the surface of EpCAMhighHCC cells, resulting in resistance to NK cell-mediated cytotoxicity. Inversely, silencing CEACAM1 restored cytotoxicity of NK cells against EpCAMhighHuh-7 cells. Moreover, neutralizing CEACAM1 on the NK cell surface enhanced killing of Huh-7 cells, suggesting that homophilic interaction of CEACAM1 is responsible for attenuated NK cell–mediated killing of CEACAM1highcells. In mouse experiments with Hepa1–6 cells, EpCAMhighHepa1–6 cells formed larger tumors and showed higher CEACAM1 expression after NK cell depletion. NK-mediated cytotoxicity was enhanced after blocking CEACAM1 expression using the anti-CEACAM1 antibody, thereby facilitating tumor regression. Moreover, CEACAM1 expression positively correlated with EpCAM expression in human HCC tissues, and serum CEACAM1 levels were also significantly higher in patients with EpCAM+HCC.ConclusionOur data demonstrated that EpCAMhighliver CSCs resist NK cell–mediated cytotoxicity by upregulation of CEACAM1 expression.

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Natural Killer Cell Dysfunction in Hepatocellular Carcinoma: Pathogenesis and Clinical Implications

Cited by 45 publications

References 150 publications

Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells

Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells

Natural killer cells in patients with hematologic malignancies, solid tumors and in recipients of hematopoietic stem cell transplantation

EpCAM-high liver cancer stem cells resist natural killer cell–mediated cytotoxicity by upregulating CEACAM1

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