NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo
Tadepally Lakshmikanth, … , Ennio Carbone, Francesco Colucci
Tadepally Lakshmikanth, … , Ennio Carbone, Francesco Colucci
Published April 6, 2009
Citation Information: J Clin Invest. 2009;119(5):1251-1263. https://doi.org/10.1172/JCI36022.
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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 8

Receptor-mediated NK cell recognition of melanoma and opportunities for immunotherapy.

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Receptor-mediated NK cell recognition of melanoma and opportunities for ...
(A) The early stages of melanoma cells are opposed by only rare resident or infiltrating NK cells, and these melanoma cells eventually metastasize to the draining LN. Although ligands for both DNAM-1 and NCRs are expressed, along with low expression of MHC class I molecules, targeting the DNAM-1 pathway might be an effective immunotherapeutic strategy at this stage, for example, by infusing autologous or allogeneic DNAM-1+ NK cells. (B) Once in the LN, the melanoma cells might undergo a weak and inefficient selection by the low cytotoxic CD56bright NK cells. (C) Hematogenous spread of melanoma cells might undergo a stronger selection by the highly cytotoxic CD56dim blood NK cells, resulting in an editing out of the melanoma cells expressing NCR ligands. (D) The melanoma cells not expressing NCR ligands escape NK cells and metastasize to visceral organs. Immunotherapeutic intervention at later stages of the disease based on the use of strong cytotoxic NK cells could be envisaged by either deliberately recruiting autologous NK cells from the patient’s pool into the LN or by adoptively transferring allogeneic NK cells from healthy donors in an attempt to halt the metastatic progression to visceral organs. This oversimplified view of melanoma progression is placed in the context of NK cell recognition and does not take into account the interactions of melanoma cells with other immune cells.