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

• Published in: International immunology 2008-07, Vol.20 (7), p.801-810
• Main Authors: Le Maux Chansac, Béatrice, Missé, Dorothée, Richon, Catherine, Vergnon, Isabelle, Kubin, Marek, Soria, Jean-Charles, Moretta, Alessandro, Chouaib, Salem, Mami-Chouaib, Fathia
• Format: Article
• Language: English
• Subjects: Antibodies, Blocking - pharmacology; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line; Cytotoxicity, Immunologic - drug effects; GPI-Linked Proteins; Histocompatibility Antigens Class I - biosynthesis; Histocompatibility Antigens Class I - immunology; Humans; Intercellular Signaling Peptides and Proteins - biosynthesis; Intercellular Signaling Peptides and Proteins - immunology; Interleukin-15 - pharmacology; Intracellular Signaling Peptides and Proteins - immunology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Killer Cells, Natural - pathology; Kynurenine 3-Monooxygenase - pharmacology; Life Sciences; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Male; Membrane Proteins - biosynthesis; Membrane Proteins - immunology; Middle Aged; NK Cell Lectin-Like Receptor Subfamily K - antagonists & inhibitors; NK Cell Lectin-Like Receptor Subfamily K - immunology; NK Cell Lectin-Like Receptor Subfamily K - metabolism; NK cell-activating receptors; NKG2DL; NSCLC; Recombinant Proteins - pharmacology; tumor-infiltrating NK cells
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxn038

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.