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Enhanced In Vivo Growth of Lymphoma Tumors in the Absence of the NK-Activating Receptor NKp46/NCR1¹

Lautenberg Center for General and Tumor Immunology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel

The in vitro elimination of virus-infected and tumor cells by NK cells is regulated by a balance between signals conveyed via specific inhibitory and activating receptors. Whether NK cells and specifically the NK-activating receptor NKp46 (NCR1 in mice) are directly involved in tumor eradication in vivo is still largely unknown. Since the NKp46/NCR1 tumor ligands have not been identified yet, we use a screening technique to identify functional ligands for NKp46/NCR1 which is based on a cell reporter assay and discover a NCR1 ligand in the PD1.6 lymphoma line. To study whether NKp46/NCR1 is important for the eradication of PD1.6 lymphoma in vivo, we used the Ncr1 knockout Ncr1^gfp/gfp mice generated by our group. Strikingly, all Ncr1 knockout mice developed growing PD1.6 tumors, whereas initial tumor growth was observed in the wild-type mice and tumors were completely rejected as time progressed. The growth of other lymphoma cell lines such as B10 and EL4 was equivalent between the Ncr1 knockout and wild-type mice. Finally, we show that PD1.6 lymphoma cells are less killed both in vitro and in vivo in the absence of NKp46/NCR1. Our results therefore reveal a crucial role for NKp46/NCR1 in the in vivo eradication of some lymphoma cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the US–Israel Bi-national Science Foundation, the Israeli Cancer Research Foundation, the Israeli Science Foundation, the European Consortium (Grants MRTN-CT-2005 and LSCH-CT-2005-518178), and the AICR. O.M. is an Edward Crown Professor of Molecular Immunology.

² Address correspondence and reprint requests to Prof. Ofer Mandelboim, The Hebrew University, Hadassah Medical School, P.O.B. 12272 Jerusalem, Israel. E-mail address: oferm{at}ekmd.huji.ac.il

³ Abbreviations used in this paper: NCR, natural cytotoxicity receptor; HA, hemagglutinin.

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