NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo
Tadepally Lakshmikanth, Shannon Burke, Talib Hassan Ali, Silvia Kimpfler, Francesco Ursini, Loredana Ruggeri, Marusca Capanni, Viktor Umansky, Annette Paschen, Antje Sucker, Daniela Pende, Veronika Groh, Roberto Biassoni, Petter Höglund, Masashi Kato, Kazuko Shibuya, Dirk Schadendorf, Andrea Anichini, Soldano Ferrone, Andrea Velardi, Klas Kärre, Akira Shibuya, Ennio Carbone, Francesco Colucci
Tadepally Lakshmikanth, Shannon Burke, Talib Hassan Ali, Silvia Kimpfler, Francesco Ursini, Loredana Ruggeri, Marusca Capanni, Viktor Umansky, Annette Paschen, Antje Sucker, Daniela Pende, Veronika Groh, Roberto Biassoni, Petter Höglund, Masashi Kato, Kazuko Shibuya, Dirk Schadendorf, Andrea Anichini, Soldano Ferrone, Andrea Velardi, Klas Kärre, Akira Shibuya, Ennio Carbone, Francesco Colucci
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Research Article Oncology

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 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.

Authors

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

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Figure 4

LN metastases are preferentially recognized by NK cells.

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LN metastases are preferentially recognized by NK cells. (A and B) Resti...
(A and B) Resting allogeneic NK cells from healthy donors were co-incubated with paired melanoma cell lines from LN and skin metastases obtained from patients Mel14 and Mel16 and subjected to cytotoxicity assays. Data are mean ± SEM of results from 6 experiments. *P < 0.05, **P < 0.005 by Student’s t test. (C and D) Autologous NK cells were co-incubated with paired melanoma cell lines from LN and skin metastases obtained from patients Mel14 and Mel16 and subjected to cytotoxicity assays. Data are from 1 experiment performed. (E) Resting allogeneic NK cells from healthy donors were co-incubated with unpaired melanoma cell lines from LN (open symbols) and skin (filled symbols) metastases obtained from different patients and subjected to cytotoxicity assays. Data are representative of 1 of 4 experiments. (F) Resting allogeneic NK cells from healthy donors were co-incubated with melanoma cell lines from LN metastases, primary uveal melanoma (PRU), and uveal melanoma liver metastases (LMs) and subjected to cytotoxicity assays. Data are representative of 1 of 3 experiments.