Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions

Garcia-Iglesias, Trinidad; Toro-Arreola, Alicia del; Albarran-Somoza, Benibelks; Toro-Arreola, Susana del; Sánchez‐Hernández, Pedro Ernesto; Ramírez‐Dueñas, Maria Guadalupe; Balderas-Peña, Luz-Ma-Adriana; Bravo-Cuéllar, Alejandro; Ortiz‐Lazareno, Pablo César; Daneri-Navarro, ́Adrián

doi:10.1186/1471-2407-9-186

Cited by 165 publications

(152 citation statements)

References 38 publications

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“…In addition, we also found that tumor-associated NK cells had significantly decreased expression of NKG2D, NKp46, perforin, and granzyme B as well as increased expression of the inhibitory receptor NKG2A. The results we have examined in murine tumor-associated NK cells correlate well with human studies which have shown that NK cells from human cervical tumors or non-small cell lung carcinoma (NSCLC) display decreased expression of NKp46 and NKG2D 29,30 . In these studies, tumor NK cells were less cytotoxic and displayed a reduced ability to produce IFN-c.…”

Section: Discussionsupporting

confidence: 73%

The breast tumor microenvironment alters the phenotype and function of natural killer cells

et al. 2015

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Natural killer (NK) cells are innate immune cells with the ability to identify and eliminate transformed cells. However, within tumors, many studies have described NK cells as non-functional. The developmental stage of tumor-associated NK cells and how this may relate to functionality has not been explored. We examined the developmental state of NK cells from polyoma middle T antigen (pyMT) transgenic mouse (MMTV-pMT) breast tumors. In pyMT tumors, NK cells were immature as evidenced by their decreased expression of DX5 and their CD27 low CD11b low phenotype. These immature NK cells also had increased expression of NKG2A and expressed low levels of NKp46, perforin, and granzyme B. In contrast, splenic NK cells isolated from the same mice maintained their maturity and their expression of activation markers. To delineate whether the tumor microenvironment directly alters NK cells, we adoptively transferred labeled NK cells and followed their activation status in both the spleen and the tumor. NK cells that arrived at the tumor had half the expression of NKp46 within three days of transfer in comparison to those which arrived at the spleen. In an effort to modify the tumor microenvironment and assess the plasticity of intratumoral NK cells, we treated pyMT tumors with IL-12 and anti-TGF-b. After one week of treatment, the maturity of tumor-associated NK cells was increased; thus, indicating that these cells possess the ability to mature and become activated. A better understanding of how NK cells are modified by the tumor microenvironment will help to develop strategies aimed at bolstering immune responses against tumors.

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Section: Discussionsupporting

confidence: 73%

The breast tumor microenvironment alters the phenotype and function of natural killer cells

et al. 2015

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“…Decreased expression of NKG2D has been observed in most cancer patients, which include breast cancer (BC), lung cancer (LC), colorectal cancer (CRC), cervical cancer (CC), pancreatic cancer (PC), gastric cancer (GC) and HCC. [26][27][28][29][30][31] With disease progression, decreased expression of NKG2D can be correlated with decreased NK cell function, most notably reduced cytotoxicity. The significantly 22,28,[34][35][36] Moreover, these alterations are not limited to activating receptors on NK cells.…”

Section: Nk Receptors In Tumorsmentioning

confidence: 99%

“…[26][27][28][29][30][31] With disease progression, decreased expression of NKG2D can be correlated with decreased NK cell function, most notably reduced cytotoxicity. The significantly 22,28,[34][35][36] Moreover, these alterations are not limited to activating receptors on NK cells. There are several studies that show that NK cell dysfunction is correlated with increased expression of the inhibitory receptor NKG2A and HLA-E. 26,37 Another study provided evidence of a significantly increased level of KIR3DL1-positive NK cells in patients with PC, GC and CRC.…”

Section: Nk Receptors In Tumorsmentioning

confidence: 99%

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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“…It has been shown that NK cells from cancer patients’ PBMCs have decreased expression of activation receptors and functional defects; 49,50 we thus investigated if entinostat treatment could increase the activation phenotype of these NK cells. PBMCs from seven heavily pretreated metastatic breast cancer patients were treated for 48 hours with a clinically relevant exposure of entinostat or DMSO.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, the fact that NK cells from heavily pretreated breast cancer patients had phenotypic changes after exposure to entinostat similar to healthy donor NK cells was a key novel finding of our study since it has been shown that cancer patients often have dysfunctional NK cells that are lacking an active phenotype. 49,50 …”

Section: Discussionmentioning

confidence: 99%

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types

et al. 2018

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Checkpoint inhibitors targeting the PD-1/PD-L1 axis are promising immunotherapies shown to elicit objective responses against multiple tumor types, yet these agents fail to benefit most patients with carcinomas. This highlights the need to develop effective therapeutic strategies to increase responses to PD-1/PD-L1 blockade. Histone deacetylase (HDAC) inhibitors in combination with immunotherapies have provided preliminary evidence of anti-tumor effects. We investigated here whether exposure of either natural killer (NK) cells and/or tumor cells to two different classes of HDAC inhibitors would augment (a) NK cell‒mediated direct tumor cell killing and/or (b) antibody-dependent cellular cytotoxicity (ADCC) using avelumab, a fully human IgG1 monoclonal antibody targeting PD-L1. Treatment of a diverse array of human carcinoma cells with a clinically relevant dose of either the pan-HDAC inhibitor vorinostat or the class I HDAC inhibitor entinostat significantly enhanced the expression of multiple NK ligands and death receptors resulting in enhanced NK cell‒mediated lysis. Moreover, HDAC inhibition enhanced tumor cell PD-L1 expression both in vitro and in carcinoma xenografts. These data demonstrate that treatment of a diverse array of carcinoma cells with two different classes of HDAC inhibitors results in enhanced NK cell tumor cell lysis and avelumab-mediated ADCC. Furthermore, entinostat treatment of NK cells from healthy donors and PBMCs from cancer patients induced an activated NK cell phenotype, and heightened direct and ADCC-mediated healthy donor NK lysis of multiple carcinoma types. This study thus extends the mechanism and provides a rationale for combining HDAC inhibitors with PD-1/PD-L1 checkpoint blockade to increase patient responses to anti-PD-1/PD-L1 therapies.

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Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions

Cited by 165 publications

References 38 publications

The breast tumor microenvironment alters the phenotype and function of natural killer cells

The breast tumor microenvironment alters the phenotype and function of natural killer cells

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

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types

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