Molecular Bases for the Regulation of NKG2D Ligands in Cancer

Huergo-Zapico, Leticia; Acebes-Huerta, Andrea; López‐Soto, Alejandro; Villa-Álvarez, Mónica; González-Rodríguez, Ana Pilar; González, Segundo

doi:10.3389/fimmu.2014.00106

Cited by 55 publications

(55 citation statements)

References 78 publications

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“…Several studies suggested that expression of activating NK cell ligands on tumors may be directly induced by oncogenes. 26 For instance, in mice ligands for the activating receptor NKG2D were described to be induced by the oncogenes c-Myc 27 or HRasV12. 28 Additionally, H-RasV12 28 , BCR-ABL 29 , HER2/ Here, we analyzed the transcriptional regulation of B7-H6 by cloning sequential 5 0 -deletion sequences of the B7-H6 gene promoter in front of a luciferase reporter gene and transfected these constructs into HeLa cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

The proto-oncogene Myc drives expression of the NK cell-activating NKp30 ligand B7-H6 in tumor cells

et al. 2016

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Natural Killer (NK) cells are innate effector cells that are able to recognize and eliminate tumor cells through engagement of their surface receptors. NKp30 is a potent activating NK cell receptor that elicits efficient NK cell-mediated target cell killing. Recently, B7-H6 was identified as tumor cell surface expressed ligand for NKp30. Enhanced B7-H6 mRNA levels are frequently detected in tumor compared to healthy tissues. To gain insight in the regulation of expression of B7-H6 in tumors, we investigated transcriptional mechanisms driving B7-H6 expression by promoter analyses. Using luciferase reporter assays and chromatin immunoprecipitation we mapped a functional binding site for Myc, a proto-oncogene overexpressed in certain tumors, in the B7-H6 promoter. Pharmacological inhibition or siRNA/shRNAmediated knock-down of c-Myc or N-Myc significantly decreased B7-H6 expression on a variety of tumor cells including melanoma, pancreatic carcinoma and neuroblastoma cell lines. In tumor cell lines from different origin and primary tumor tissues of hepatocellular carcinoma (HCC), lymphoma and neuroblastoma, mRNA levels of c-Myc positively correlated with B7-H6 expression. Most importantly, upon inhibition or knock-down of c-Myc in tumor cells impaired NKp30-mediated degranulation of NK cells was observed. Thus, our data imply that Myc driven tumors could be targets for cancer immunotherapy exploiting the NKp30/B7-H6 axis.

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Section: Discussionmentioning

confidence: 99%

The proto-oncogene Myc drives expression of the NK cell-activating NKp30 ligand B7-H6 in tumor cells

et al. 2016

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“…The expression of NKG2D ligands is an indicator of cellular stress and can be induced by viral infection or malignant transformation. In normal cells, NKG2D ligands are expressed at low to undetectable levels, avoiding autoimmunity . NKG2D ligands can be upregulated in several types of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of natural killer group 2 member D ligands predicts favorable prognosis in cholangiocarcinoma

et al. 2016

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The natural killer group 2 member D (NKG2D) receptor and its ligands are important mediators of immune responses to tumors. NKG2D ligands are overexpressed in several malignant tumor types; however, the prognostic value of these ligands is unclear. Here, we aimed to elucidate the role of NKG2D ligands in extrahepatic cholangiocarcinoma (EHCC). We therefore investigated the expression of the NKG2D receptor and its ligands MHC class I chain-related proteins A and B (MICA ⁄ B), unique long 16 binding protein (ULBP) 1, and ULBP2 ⁄ 5 ⁄ 6 in resected specimens from 82 patients with EHCC. All NKG2D ligands were highly expressed in EHCC. High expression of MICA ⁄ B or ULBP2 ⁄ 5 ⁄ 6 correlated with overall and disease-free survival. In contrast, high expression of ULBP1 was significantly associated with improved overall survival, but not disease-free survival. Concurrent high expression of multiple NKG2D ligands revealed significantly better overall and disease-free survival than that observed with the overexpression of any one NKG2D ligand. Co-expression of multiple NKG2D ligands was an independent prognostic indicator of improved survival. Furthermore, co-overexpression of multiple NKG2D ligands was significantly correlated with high expression of the NKG2D receptor. Inhibiting interactions between multiple NKG2D ligands and the NKG2D receptor might be a promising approach for controlling cancer progression and improving patient prognosis in EHCC.C holangiocarcinoma is a malignant cancer that originates from epithelial cells in bile ducts.(1,2) It is classified as intrahepatic or extrahepatic, and EHCC is subcategorized into perihilar and distal forms. (3,4) Although EHCC is relatively uncommon in North America and Europe, its incidence and mortality rates continue to rise worldwide. (5,6) This is especially true in Japan, where the annual mortality due to EHCC was approximately 12 000 in 2013.(7) There is no curative treatment for cholangiocarcinoma except surgical resection and, despite recent advances in surgical techniques, recurrence occurs in most patients even after resection. Regrettably, post-resection 5-year survival rates are only 20-30%.(8) Therefore, the identification of new therapeutic targets and biomarkers is critical for improving outcomes in patients with cholangiocarcinoma.We previously reported that epithelial-mesenchymal transition-related factors, such as epithelial ⁄ neural-cadherin and forkhead box protein C2, were correlated with the prognosis and progression of EHCC.(9,10) Due to recent advancements in cancer immunotherapeutics, the editors of Science named cancer immunotherapy as the Breakthrough of the Year in 2013.(11) In particular, the immune checkpoint blockade approach involving the use of the anti-cytotoxic T-lymphocyte antigen 4 antibody and the anti-PD-1 antibody were significant recent developments. The US FDA has approved ipilimumab, pembrolizumab, and nivolumab for the treatment of metastatic melanoma, and the Pharmaceuticals and Medical Devices Agency in Japan has approved nivol...

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“…In humans these ligands are MHC class-I chain related proteins (MIC) A, MICB and UL16 binding protein (ULBP) 1–6 [27–29]. Paradoxically, the presence of the soluble form of NKG2DLs generates an inhibitory action on NK cells.…”

Section: Introductionmentioning

confidence: 99%

Soluble Ligands for the NKG2D Receptor Are Released during Endometriosis and Correlate with Disease Severity

et al. 2015

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BackgroundEndometriosis is a benign gynaecological disease. Abundant bulk of evidence suggests that patients with endometriosis have an immunity dysfunction that enables ectopic endometrial cells to implant and proliferate. Previous studies show that natural killer cells have a pivotal role in the immune control of endometriosis.Methods and FindingsThis is a prospective laboratory study conducted in a tertiary-care university hospital between January 2011 and April 2013. We investigated non-pregnant, younger than 42-year-old patients (n= 202) during surgery for benign gynaecological conditions. After complete surgical exploration of the abdominopelvic cavity, 121 women with histologically proven endometriosis and 81 endometriosis-free controls women were enrolled. Patients with endometriosis were classified according to a surgical classification in three different types of endometriosis: superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA) and deep infiltrating endometriosis (DIE). Peritoneal fluid samples were obtained from all study participants during the surgery in order to detect soluble NKG2D ligands (MICA, MICB and ULBP-2). When samples with undetectable peritoneal fluid levels of MICA, MICB and ULBP-2 were excluded, MICA ratio levels were significantly higher in endometriosis patients than in controls (median, 1.1 pg/mg; range, 0.1–143.5 versus median, 0.6 pg/mg; range, 0.1–3.5; p=0.003). In a similar manner peritoneal fluid MICB levels were also increased in endometriosis-affected patients compared with disease-free women (median, 4.6 pg/mg; range, 1.2–4702 versus median, 3.4 pg/mg; range, 0.7–20.1; p=0.001). According to the surgical classification, peritoneal fluid soluble MICA, MICB and ULBP-2 ratio levels were significantly increased in DIE as compared to controls (p=0.015, p=0.003 and p=0.045 respectively). MICA ratio levels also correlated with dysmenorrhea (r=0.232; p=0.029), total rAFS score (r=0.221; p=0.031) and adhesions rAFS score (r=0.221; p=0.031).ConclusionsWe demonstrate a significant increase of peritoneal fluid NKG2D ligands in women with endometriosis especially in those cases presenting DIE. This study suggests that NKG2D ligands shedding is a novel pathway in endometriosis complex pathogenesis that impairs NK cell function.

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Molecular Bases for the Regulation of NKG2D Ligands in Cancer

Cited by 55 publications

References 78 publications

The proto-oncogene Myc drives expression of the NK cell-activating NKp30 ligand B7-H6 in tumor cells

The proto-oncogene Myc drives expression of the NK cell-activating NKp30 ligand B7-H6 in tumor cells

Overexpression of natural killer group 2 member D ligands predicts favorable prognosis in cholangiocarcinoma

Soluble Ligands for the NKG2D Receptor Are Released during Endometriosis and Correlate with Disease Severity

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