NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo

Lakshmikanth, Tadepally; Burke, Shannon; Ali, Talib Hassan; Kimpfler, Silvia; Ursini, Francesco; Ruggeri, Loredana; Capanni, Marusca; Umansky, Viktor; Paschen, Annette; Sucker, Antje; Pende, Daniela; Groh, Veronika; Biassoni, Roberto; Höglund, Petter; Kato, Masashi; Shibuya, Kazuko; Schadendorf, Dirk; Anichini, Andrea; Ferrone, Soldano; Velardi, Andrea; Kärre, Klas; Shibuya, Akira; Carbone, Ennio; Colucci, Francesco

doi:10.1172/jci36022

Cited by 304 publications

(316 citation statements)

References 36 publications

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“…Alternatively, it is also possible that NKp46/NCR1 inhibits metastases detachment from the primary tumors, or that it kills the disseminating metastases on their way to the lungs. Additionally, it is possible that the location of the primary tumors is important, as in previous models the cancer cells were s.c. injected into the flank and NK cells migrated to these tumors (12)(13)(14), whereas here tumor cells were injected into the footpad to enable spontaneous metastasis. Finally, it is possible that the circulating tumor cells transiently changed their properties during their migration to the lungs and that this is NCR1-dependent.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of NKp46/NCR1 by its unknown tumor ligand(s) can lead either to IFN-g secretion (14), to enhanced killing, or to both (7,8,12). To test which of these mechanisms is activated when NK cells interact with B16 or D122 cells we used the NCR1 gfp/gfp (KO) and the immune competent NCR1 +/gfp (Het) mice, (7), in a CD107a (LAMP-1) mobilization assay (16).…”

Section: Nkp46/ncr1-dependent Nk Degranulation Following Incubation Wmentioning

confidence: 99%

“…Most cancer patients often succumb to metastasis, which is the major cause of cancer-related lethality (11). NKp46/NCR1 was shown to take an important part in controlling the spread of various primary tumors, including melanoma, lymphoma, carcinoma, and carcinogen-induced fibrosarcoma (3-methylcholanthrene [MCA]-induced) (12)(13)(14). However, it is still unknown whether any of the NK activating receptors is directly involved in the regulation of spontaneous tumor metastasis.…”

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confidence: 99%

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Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

Glasner¹,

Ghadially²,

Gur³

et al. 2012

The Journal of Immunology

140

119

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NK cells employ a variety of activating receptors to kill virally infected and tumor cells. Prominent among these receptors are the natural cytotoxicity receptors (NCRs) (NKp30, NKp44, and NKp46), of which only NKp46 has a mouse ortholog (NCR1). The tumor ligand(s) of NKp46/NCR1 is still unknown, but it was shown that the human NKp46 and the mouse NCR1 are involved in tumor eradication both in vitro and in vivo. Whether any of the NK activating receptors is involved in the prevention of tumor metastasis is unknown. To address this question, we studied the activity of the NK cell receptor NKp46/NCR1 in two spontaneous metastasis models, the B16F10.9 melanoma (B16) and the Lewis lung carcinoma (D122) in the NCR1 knockout mouse that was generated by our group, in various in vitro and in vivo assays. We demonstrated that all B16 and D122 tumors, including those generated in vivo, express an unknown ligand(s) for NKp46/NCR1. We have characterized the properties of the NKp46/NCR1 ligand(s) and demonstrated that NKp46/NCR1 is directly involved in the killing of B16 and D122 cells. Importantly, we showed in vivo that NKp46/NCR1 plays an important role in controlling B16 and D122 metastasis. Thus, to our knowledge, in this study we provide the first evidence for the direct involvement of a specific NK killer receptor in preventing tumor metastasis.

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Section: Discussionmentioning

confidence: 99%

Section: Nkp46/ncr1-dependent Nk Degranulation Following Incubation Wmentioning

confidence: 99%

mentioning

confidence: 99%

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Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

Glasner¹,

Ghadially²,

Gur³

et al. 2012

The Journal of Immunology

140

119

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“…Moreover, we found that intrahepatic frequency of NKp46 High NK cells inversely correlated with HCV loads. Whether NKp46 recognizes a HCV-derived protein [17][18][19][20][21] or interacts with a yet unknown NKp46 ligand, as has been suggested for malignant transformed cells, 40,41 remains to be clarified. However, blocking of NKp46 significantly reduced the capability of both circulating and intrahepatic NK cells to block HCV replication, suggesting a role of NKp46 in the regulation of anti-HCV immune responses.…”

Section: Nk Cells (Supportingmentioning

confidence: 99%

Natural killer p46^Highexpression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis

et al. 2012

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Natural killer (NK) cells play a role in the early control and natural course of hepatitis C virus (HCV) infection. NK cell function is regulated by a multitude of receptors, including activating NKp46 receptor. However, reports on NKp46 in hepatitis C are controversial. Therefore, we investigated the hepatic recruitment and function of NKp46(1) NK cells, considering differential surface expression of NKp46 resulting in NKp46 High and NKp46 Dim subsets. Intra-and extrahepatic NK-cell subsets from HCV-infected patients were characterized by flow cytometry. Cytotoxic activity and interferon-gamma (IFN-c) secretion were studied using K-562, P815, and primary hepatic stellate cells as targets. Anti-HCV activity of NK-cell subsets was studied using the replicon system. Density of NKp46 surface expression clearly segregated NKp46 Dim and NKp46 High subsets, which differed significantly with respect to the coexpression of maturation markers and NK-cell receptors. More important, NKp46 High NK cells showed a higher cytolytic activity and stronger IFN-c secretion than NKp46 Dim NK cells. Accordingly, NKp46 High NK cells efficiently blocked HCV replication in vitro. Blocking experiments confirmed an important role for the NKp46 receptor. Furthermore, we found an intrahepatic accumulation of NKp46 High NK cells. Of note, high cytolytic activity of NKp46 High NK cells was also confirmed in the intrahepatic NK-cell population, and the frequency of intrahepatic NKp46 High NK cells was inversely correlated with HCV-RNA levels and fibrosis stage. Conclusions: NKp46 High expression defines a specific NK-cell subset that may be involved in both the suppression of HCV replication and HCV-associated liver damage underpinning the role of NK cells in the immunopathogenesis of HCV. (HEPATOLOGY 2012;56:1201-1213 See Editorial on Page 1197 I nfection with the hepatitis C virus (HCV) often results in chronic liver disease. Elimination of HCV infection requires the coordinated function of the innate and the adaptive immune system. Natural killer (NK) cells constitute a major component of the intrahepatic lymphocyte pool. In contrast to the peripheral blood, which contains approximately 5%-10% NK cells, intrahepatic lymphocytes comprise approximately 30% NK cells, and the percentage of intrahepatic NK cells may increase >50% in liver diseases. 1 Immunogenetic analyses indicate that NK cells may influence the outcome of acute HCV infection as well as immunopathogenesis in chronic hepatitis C (CHC). 2 Accordingly, in vitro studies suggest that NK cells are able to recognize and kill HCV-infected hepatocytes in vivo. 3 However, published data on phenotype and function of NK cells in HCV infection are controversial. [4][5][6][7][8][9][10][11][12][13]

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“…19 Indeed, DNAM-1 triggers NK cell killing of freshly isolated ovarian carcinoma and neuroblastoma cells 20,21 and is required for killing and control of melanoma metastases. 22,23 Similarly, mice lacking DNAM-1 exhibit accelerated growth of DNAM-1 ligandexpressing tumors. 24 Thus, DNAM-1 appears to be a key regulator of NK-cell-mediated cancer immunosurveilance.…”

Section: Introductionmentioning

confidence: 99%

Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing

et al. 2016

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Acute myeloid leukemia (AML) is associated with poor natural killer (NK) cell function through aberrant expression of NK-cell-activating receptors and their ligands on tumor cells. These alterations are thought to promote formation of inhibitory NK-target cell synapses, in which killer cell degranulation is attenuated. Allogeneic stem cell transplantation can be effective in treating AML, through restoration of NK cell lytic activity. Similarly, agents that augment NK-cell-activating signals within the immunological synapse may provide some therapeutic benefit. However, the receptor-ligand interactions that critically dictate NK cell function in AML remain undefined. Here, we demonstrate that CD112/CD155 expression is required for DNAM-1-dependent killing of AML cells. Indeed, the low, or absent, expression of CD112/CD155 on multiple AML cell lines resulted in failure to stimulate optimal NK cell function. Importantly, isolated clones with low CD112/155 expression were resistant to NK cell killing while those expressing abundant levels of CD112/155 were highly susceptible. Attenuated NK cell killing in the absence of CD112/CD155 originated from decreased NK-target cell conjugation. Furthermore, we reveal by time-lapse microscopy, a significant increase in NK cell 'failed killing' in the absence of DNAM-1 ligands. Consequently, NK cells preferentially lysed ligandexpressing cells within heterogeneous populations, driving clonal selection of CD112/CD155-negative blasts upon NK cell attack. Taken together, we identify reduced CD155 expression as a major NK cell escape mechanism in AML and an opportunity for targeted immunotherapy.

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NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo

Abstract: NK cells use a variety of receptors to detect abnormal cells, including

Cited by 304 publications

References 36 publications

Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

Natural killer p46^Highexpression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis

Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing

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NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo

Abstract: NK cells use a variety of receptors to detect abnormal cells, including

Cited by 304 publications

References 36 publications

Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

Natural killer p46Highexpression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis

Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing

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Natural killer p46^Highexpression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis