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

Abstract

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.

Anti-HIV Antibody–Dependent Activation of NK Cells Impairs NKp46 Expression

“…The data presented in this article corroborate the previous finding of de- creased CD16 expression and demonstrate that CD16-mediated activation reduces the expression of the key activating NK cell NKp46 receptor. The NKp46 receptor was demonstrated to be essential for the in vitro functionality of NK cells (15) and, consequently, was suggested to be crucial to the in vivo immunity conferred by NK cells against tumors and viruses (24,25). The level of NKp46 expressed on the NK cell surface is associated with the magnitude of the response elicited upon ligation (15).…”

“…Alterations in the expression of these receptors likely have a significant negative impact upon the ability to respond to infections and malignant conditions. For example, natural cytotoxicity receptors are involved in recognizing ligands present during viral infections, as well as malignancies (23)(24)(25). Experiments in an NKp46-knockout mouse model raised the possibility that the receptor is essential for controlling both cancer metastasis and influenza infection (24,25).…”

“…For example, natural cytotoxicity receptors are involved in recognizing ligands present during viral infections, as well as malignancies (23)(24)(25). Experiments in an NKp46-knockout mouse model raised the possibility that the receptor is essential for controlling both cancer metastasis and influenza infection (24,25). Although the exact mechanism(s) for the HIV-related in vivo alterations in NK cell receptors have not been elucidated, in vitro studies (26)(27)(28)(29) demonstrated that similar NK cell alterations can be induced through activation.…”

Conditional ablation of NKp46+ cells using a novel Ncr1greenCre mouse strain: NK cells are essential for protection against pulmonary B16 metastases

“…The fact that tissue-specific NK-cell populations with unique transcription factor requirements for their development have been described in liver [21][22][23], thymus [37], skin and uterus [23], suggests that part of the observed diversity might be due to the presence of separate NK-cell lineages. However, more recent data suggest that these tissue-resident NK cells might be related to non-NK ILC1 sharing with NK cells some phenotypic features (NKp46 and NK1.1 expression) while lacking others (expression of NK-cell markers like Ly49 molecules and DX5) [24,25] Ample evidence suggests that NK cells are important for the immune response to B16 melanoma [15,[39][40][41]. In humans and mice, primary melanomas as well as melanoma derived cell lines have been shown to express ligands for NKp46 and DNAM1 explaining their susceptibility to NK-cell mediated lysis [39].…”

“…Ample evidence suggests that NK cells are important for the immune response to B16 melanoma [15,[39][40][41]. In humans and mice, primary melanomas as well as melanoma derived cell lines have been shown to express ligands for NKp46 and DNAM1 explaining their susceptibility to NK-cell mediated lysis [39].…”