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International Immunology Advance Access published online on April 25, 2008
International Immunology, doi:10.1093/intimm/dxn038
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Potentiation of NK cell-mediated cytotoxicity in human lung adenocarcinoma: role of NKG2D-dependent pathway

Béatrice Le Maux Chansac1, Dorothée Missé2, Catherine Richon3, Isabelle Vergnon1, Marek Kubin4, Jean-Charles Soria5, Alessandro Moretta6, Salem Chouaib1 and Fathia Mami-Chouaib1

1 Institut National de la Santé et de la Recherche Médicale U753, Laboratoire ‘Immunologie des Tumeurs humaines: Interaction Effecteurs Cytotoxiques-Système Tumoral’, Institut Fédératif de Recherche-54, Institut Gustave Roussy, 94805 Villejuif Cedex, France
2 Unité de Génétique et Evolution des Maladies Infectieuses, UMR CNRS/IRD 2724, Institut de Recherche pour le Développement, 34394 Montpellier, France
3 Unité de Génomique Fonctionnelle, Institut Fédératif de Recherche-54, Institut Gustave Roussy, 94805 Villejuif Cedex, France
4 Amgen, Seattle, WA 98101, USA
5 Département de Médecine, Institut Gustave Roussy, 94805 Villejuif Cedex, France
6 Dipartimento di Medicina Sperimentale Sezione di Istologia and Centro di Eccellenza per le Ricerche Biomediche, Università di Genova, 16132 Genova, Italy

Correspondence to: Correspondence to: F. Mami-Chouaib; E-mail: cfathia{at}igr.fr

Natural cytotoxicity receptors and NKG2D correspond to major activating receptors involved in triggering of tumor cell lysis by human NK cells. In this report, we investigated the expression of NKG2D ligands (NKG2DLs), MHC class I-related chain (MIC) A, MICB and UL16-binding proteins 1, 2 and 3, on a panel of human non-small-cell lung carcinoma cell lines, and we analyzed their role in tumor cell susceptibility to NK cell lysis. Although adenocarcinoma (ADC) cells expressed heterogeneous levels of NKG2DLs, they were often resistant to NK cell-mediated killing. Resistance of a selected cell line, ADC-Coco, to allogeneic polyclonal NK cells and autologous NK cell clones correlated with shedding of NKG2DLs resulting from a matrix metalloproteinase (MMP) production. Treatment of ADC-Coco cells with a MMP inhibitor (MMPI) combined with IL-15 stimulation of autologous NK cell clones lead to a potentiation of NK cell-mediated cytotoxicity. This lysis is mainly NKG2D mediated, since it is abrogated by anti-NKG2D-neutralizing mAb. These results suggest that MMPIs, in combination with IL-15, may be useful for overcoming tumor cell escape from the innate immune response.

Keywords: NK cell-activating receptors, NKG2DL, NSCLC, tumor-infiltrating NK cells

Transmitting editor: G. Trinchieri

Received 26 October 2007, accepted 27 March 2008.


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