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Tumor Immunoediting by Nkp46 Tumor Immunoediting by NKp46 Moran Elboim, Roi Gazit, Chamutal Gur, Hormas Ghadially, Gili Betser-Cohen and Ofer Mandelboim This information is current as J Immunol 2010; 184:5637-5644; Prepublished online 19 of October 7, 2021. April 2010; doi: 10.4049/jimmunol.0901644 http://www.jimmunol.org/content/184/10/5637 Downloaded from References This article cites 37 articles, 13 of which you can access for free at: http://www.jimmunol.org/content/184/10/5637.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 7, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Tumor Immunoediting by NKp46 Moran Elboim,* Roi Gazit,† Chamutal Gur,* Hormas Ghadially,* Gili Betser-Cohen,* and Ofer Mandelboim* NK cells interact with a wide variety of hazardous cells including pathogen-infected and tumor cells. NKp46 is a specific NK killer receptor that recognizes various influenza hemagglutinins and unknown tumor ligands. It was recently shown that NKp46 plays a significant role in the in vivo eradication of tumor cells; however, the role played by NKp46 in vivo with regard to tumor de- velopment is still unclear. In this study, we used the 3-methylcholanthrene (MCA)-induced fibrosarcoma model in NKp46-deficient mice to test the NKp46 recognition of carcinogen-induced tumors. We show that although the rate of MCA-induced tumor formation was similar in the presence and in the absence of NKp46, the expression of its unknown ligands was NKp46 dependent. The unknown NKp46 ligands were nearly absent in tumors that originated in wild-type mice, whereas they were detected in tumors that originated in the NKp46-deficient mice. We demonstrate that the interactions between NKp46 and its MCA tumor-derived ligands lead to the secretion of IFN-g but not to the elimination of the MCA-derived tumor cells. In addition, we show that the in vivo growth of Downloaded from MCA-derived tumor cells expressing high levels of the NKp46 ligands is NKp46 and IFN-g dependent. Thus, we present in this study a novel NKp46-mediated mechanism of tumor editing. The Journal of Immunology, 2010, 184: 5637–5644. atural killer cells are innate lymphocytes able to quickly NCR1 receptor in the KO mice is impaired (7). We have demonstrated respond to a wide range of transformed and pathogen- that the NCR1 KO mice are sensitive to influenza infection, thus infected cells (1–3). The activity of NK cells is controlled confirming in vivo the importance of the NKp46/NCR1-HA inter- N http://www.jimmunol.org/ by a balance of signals delivered by inhibitory and activating re- actions. Although the function of NK cells against viral infections was ceptors (1, 4). The main activating receptors include NKp46, studied in detail (1, 15, 16), only limited number of studies in- NKp44, and NKp30 (collectively known as the natural cytotoxicity vestigated the in vivo function of NKp46 against tumors, mainly by receptors [NCRs]), NKp80, 2B4, and NKG2D (5, 6). In mice, using tumor cell lines (17, 18).Thus, whether NKp46 is alsoimportant NKG2D and 2B4 are present; however, the only functional member for the growth of carcinogen-induced tumors and what would be the of the NCRs is the mouse ortholog of the human NKp46, named effect of the NKp46 on tumor immunoediting was not investigated. NCR1 (5, 7). Only a few ligands were identified for the activating The immune response against developing tumors was studied in NK receptors. These ligands are either tumor derived, such as B7- detail using the MCA model (19, 20). Smyth and colleagues (20) H6, an NKp30 ligand, stress induced, such as the ligands for define three stages of tumor immunoediting: elimination, equilib- by guest on October 7, 2021 NKG2D, or self-ligands, such as AICL for NKp80 and BAT3 for rium, and escape. They demonstrated that the major immune pop- NKp30 (6, 8–11). With regard to the NCRs, we have demonstrated ulations involved in tumor immunoediting are T cells. The in- that the viral hemagglutinin (HA) proteins of various influenza volvement of NK cells in immunoediting has so far been studied strains interact with the human NKp44 and NKp46 and with the only in relation to NKG2D and DNAM1 (19, 21, 22). It was shown mouse NCR1 and that these interactions lead to increased killing of that the MCA-induced tumors were more frequently observed influenza-infected cells (7, 12, 13). In addition, we showed that in mice treated with blocking anti-NKG2D Abs (22). In contrast, NKp30 interacts with the HCMV’s pp65 protein, leading to the another report failed to observe an increased incidence of MCA- inhibition of killing by NK cells (14). induced sarcomas in NKG2D-deficient mice (19). Moreover, be- Our group knocked out the Ncr1 gene and inserted the GFP re- cause NKG2D is also expressed by several T cell subsets (10), porter gene instead (7). Almost all NK cells in the knockout (KO) the effect of a specific NK cell receptor such as NKp46 on the de- and heterozygous mice are labeled green, and the function of the velopment of carcinogen-induced tumors and on tumor immuno- editing remains obscure. By using the MCA-induced carcinogenesis model in Ncr1-deficient mice, we demonstrate in this study a tumor *Lautenberg Center for General and Tumor Immunology, Institute for Medical immunoediting mechanism aimed at reducing the NCR1-dependent Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, † IFN-g secretion during tumor development. Israel; and Immune Disease Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115 Received for publication May 27, 2009. Accepted for publication March 14, 2010. Materials and Methods This work was supported by grants from the Israeli Science Foundation, the Israeli Mice Science Foundation (Morasha), a Croatia Israel research grant, a MOST-DKFZ re- All experiments were performed using 8- to 12-wk-old C57BL/6 mice. The search grant, the European Consortium (Grant MRTN-CT-2005), the Rosetrees Trust, generation of the Ncr1gfp/gfp mice was described previously (7). IFN-g– the Israel Cancer Association (Grant 20100003), and the Association for International tm1Ts Cancer Research (all to O.M). O.M is a Crown Professor of Molecular Immunology. deficient mice (B6.129S7-Ifng /J) were obtained from The Jackson Laboratory (Bar Harbor, ME). All experiments were performed in the Address correspondence and reprint requests to Prof. Ofer Mandelboim, Lautenberg specific pathogen-free unit of the Hadassah Medical School (Ein Kerem, Center for General and Tumor Immunology, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, 91120 Jerusalem, Israel. Jerusalem), according to the guidelines of the ethical committee. E-mail address: [email protected] Carcinogenesis Abbreviations used in this paper: HA, hemagglutinin; NCR, natural cytotoxicity re- ceptor; poly(I):poly(C), polyinosinic:polycytidylic acid. Mice were injected i.m. with 50, 25, or 5 mg MCA (Sigma-Aldrich, St. Louis, MO) emulsified in olive oil by heating in boiling water. Tumor Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 growth was examined weekly for a period of at least 200 d. www.jimmunol.org/cgi/doi/10.4049/jimmunol.0901644 5638 TUMOR IMMUNOEDITING BY NKp46 Generation of MCA-induced cell lines cells were labeled with Vybrant DiD. A total of 2 3 106 cells of each of the cell type were mixed in 400 ml PBS and injected into the tail vein of C57BL/6 Two weeks after tumor appearance, the tumors were removed, and part of Ncr1+/+ or Ncr1gfp/gfp mice.Lungswereexplanted3hlater.Single-cell the tumor was taken for digestion by trypsin for 5 min. Following this suspensions were obtained by using a cell strainer, and fluorescence was trypsin treatment, tumors were mashed in a culture dish, and RPMI 1640 analyzed by flow cytometry. The ratio of the tested MCA-induced cell lines medium was added. After an overnight incubation in 37˚C and 5% CO2, target cells to the internal control HeLa cells was calculated. tumor clumps were removed, and the remaining cells were used as tumor- derived cell lines that were grown in RPMI 1640 medium supplemented CD107a assays with 10% FCS and 1% sodium pyruvate, glutamine, nonessential amino acids, and penicillin-streptomycin solution. Mice were injected i.p with 200 mg poly(I):poly(C), and spleens were removed 18 h later. NK cells were isolated from splenocytes using the Fusion proteins and flow cytometry mouse NK isolation kit (Miltenyi Biotec, Auburn, CA) and an autoMACS instrument according to the manufacturer’s instruction. NK cells (5 3 105) The NCR1-Ig, NKp46-Ig, and NKG2D-Ig fusion proteins were generated in were coincubated with the indicated target cells in a ratio of 1:1 in the COS-7 cells and purified by affinity chromatography using a protein G presence of 0.1 mg of an allophycocyanin-conjugated CD107a Ab (1D4B; column, as described previously (13). The staining of cell lines was vi- Southern Biotechnology Associates, Birmingham, AL) for 2 h.
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