Le Maux Chansac Béatrice, Missé Dorothée, Richon Catherine, Vergnon Isabelle, Kubin Marek, Soria Jean-Charles, Moretta Alessandro, Chouaib Salem, Mami-Chouaib Fathia
Institut National de Santé et de 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.
Int Immunol. 2008 Jul;20(7):801-10. doi: 10.1093/intimm/dxn038. Epub 2008 Apr 25.
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.
自然细胞毒性受体和NKG2D对应于参与人类NK细胞触发肿瘤细胞裂解的主要激活受体。在本报告中，我们研究了一组人非小细胞肺癌细胞系上NKG2D配体（NKG2DLs）、MHC I类相关链（MIC）A、MICB以及UL16结合蛋白1、2和3的表达情况，并分析了它们在肿瘤细胞对NK细胞裂解敏感性中的作用。尽管腺癌细胞（ADC）表达的NKG2DLs水平各异，但它们通常对NK细胞介导的杀伤具有抗性。所选细胞系ADC-Coco对同种异体多克隆NK细胞和自体NK细胞克隆的抗性与基质金属蛋白酶（MMP）产生导致的NKG2DLs脱落有关。用MMP抑制剂（MMPI）处理ADC-Coco细胞并联合IL-15刺激自体NK细胞克隆，可增强NK细胞介导的细胞毒性。这种裂解主要由NKG2D介导，因为它可被抗NKG2D中和单克隆抗体消除。这些结果表明，MMPIs与IL-15联合使用可能有助于克服肿瘤细胞逃避先天免疫反应。
