Journal Article

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

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

2009

Overview

NK cells use a variety of receptors to detect abnormal cells, including tumors and their metastases. However, in the case of melanoma, it remains to be determined what specific molecular interactions are involved and whether NK cells control metastatic progression and/or the route of dissemination. Here we show that human melanoma cell lines derived from LN metastases express ligands for natural cytotoxicity receptors (NCRs) and DNAX accessory molecule-1 (DNAM-1), two emerging NK cell receptors key for cancer cell recognition, but not NK group 2 member D (NKG2D). Compared with cell lines derived from metastases taken from other anatomical sites, LN metastases were more susceptible to NK cell lysis and preferentially targeted by adoptively transferred NK cells in a xenogeneic model of cell therapy. In mice, DNAM-1 and NCR ligands were also found on spontaneous melanomas and melanoma cell lines. Interference with DNAM-1 and NCRs by antibody blockade or genetic disruption reduced killing of melanoma cells. Taken together, these results show that DNAM-1 and NCRs are critical for NK cell-mediated innate immunity to melanoma cells and provide a background to design NK cell-based immunotherapeutic strategies against melanoma and possibly other tumors.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Antibodies - immunology / Antibodies - pharmacology / Antigens / Antigens, Differentiation, T-Lymphocyte - immunology / Antigens, Differentiation, T-Lymphocyte - metabolism / Antigens, Ly - genetics / Antigens, Ly - metabolism / Biomedical research / Care and treatment / Cell Line, Tumor / Cytotoxicity / Cytotoxicity Tests, Immunologic / Cytotoxicity, Immunologic - drug effects / Cytotoxicity, Immunologic - immunology / DNA-Binding Proteins - genetics / Genetic aspects / Health aspects / Humans / Immune system / Immunoglobulins / Immunology / Immunotherapy / Immunotherapy, Adoptive - methods / Interleukin Receptor Common gamma Subunit - genetics / Killer cells / Killer Cells, Natural - immunology / Killer Cells, Natural - metabolism / Killer Cells, Natural - transplantation / Ligands / Lymphatic Metastasis - immunology / Lymphocyte Function-Associated Antigen-1 - metabolism / Lymphoma / Melanoma / Melanoma - immunology / Melanoma - metabolism / Melanoma - pathology / Melanoma - therapy / Melanoma, Experimental - metabolism / Metastasis / Mice / Mice, Inbred NOD / Mice, Inbred Strains / Mice, Knockout / Mice, SCID / Mice, Transgenic / Natural Cytotoxicity Triggering Receptor 1 - genetics / Natural Cytotoxicity Triggering Receptor 1 - metabolism / Natural Killer T-Cells - immunology / Patients / Proteins / Receptors, Natural Cytotoxicity Triggering - immunology / Receptors, Natural Cytotoxicity Triggering - metabolism / Skin cancer / T Lineage-Specific Activation Antigen 1 / Tumors / Xenograft Model Antitumor Assays