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* Laboratoire Cytokines et Immunologie des Tumeurs humaines, U487 Institut National de la Santé et de la Recherche Médicale,
Unité mixte de Recherche 8121, Centre national de la Recherche scientifique (CNRS),
Unité Mixte de Recherche 8126, CNRS,
Département de Médecine, Institut Gustave Roussy, Villejuif, France;
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Dipartimento di Medicina Sperimentale Sezione di Istologia and Centro di Eccellenza per le Ricerche Biomediche, Università di Genova, Genova, Italy;
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Département de Chirurgie thoracique, Institut Montsouris, Paris, France; and
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Amgen, Seattle, WA 98101
NK cells are able to discriminate between normal cells and cells that have lost MHC class I (MHC-I) molecule expression as a result of tumor transformation. This function is the outcome of the capacity of inhibitory NK receptors to block cytotoxicity upon interaction with their MHC-I ligands expressed on target cells. To investigate the role of human NK cells and their various receptors in the control of MHC-I-deficient tumors, we have isolated several NK cell clones from lymphocytes infiltrating an adenocarcinoma lacking 
2-microglobulin expression. Unexpectedly, although these clones expressed NKG2D and mediated a strong cytolytic activity toward K562, Daudi and allogeneic MHC-class I+ carcinoma cells, they were unable to lyse the autologous MHC-I– tumor cell line. This defect was associated with alterations in the expression of natural cytotoxicity receptor (NCR) by NK cells and the NKG2D ligands, MHC-I-related chain A, MHC-I-related chain B, and UL16 binding protein 1, and the ICAM-1 by tumor cells. In contrast, the carcinoma cell line was partially sensitive to allogeneic healthy donor NK cells expressing high levels of NCR. Indeed, this lysis was inhibited by anti-NCR and anti-NKG2D mAbs, suggesting that both receptors are required for the induced killing. The present study indicates that the MHC-I-deficient lung adenocarcinoma had developed mechanisms of escape from the innate immune response based on down-regulation of NCR and ligands required for target cell recognition.
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