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* Laboratorio de Inmunogenética, Hospital de Clínicas and Departamento de Microbiología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina;
Centro de Investigaciones Oncológicas, Fundación para la Investigación y Prevención del Cáncer, Buenos Aires, Argentina; and
Fundación Instituto Leloir, Buenos Aires, Argentina
Most tumors grow in immunocompetent hosts despite expressing NKG2D ligands (NKG2DLs) such as the MHC class I chain-related genes A and B (MICA/B). However, their participation in tumor cell evasion is still not completely understood. Here we demonstrate that several human melanomas (cell lines and freshly isolated metastases) do not express MICA on the cell surface but have intracellular deposits of this NKG2DL. Susceptibility to NK cell-mediated cytotoxicity correlated with the ratio of NKG2DLs to HLA class I molecules but not with the amounts of MICA on the cell surface of tumor cells. Transfection-mediated overexpression of MICA restored cell surface expression and resulted in an increased in vitro cytotoxicity and IFN-
secretion by human NK cells. In xenografted nude mice, these melanomas exhibited a delayed growth and extensive in vivo apoptosis. Retardation of tumor growth was due to NK cell-mediated antitumor activity against MICA-transfected tumors, given that this effect was not observed in NK cell-depleted mice. Also, mouse NK cells killed MICA-overexpressing melanomas in vitro. A mechanistic analysis revealed the retention of MICA in the endoplasmic reticulum, an effect that was associated with accumulation of endoH-sensitive (immature) forms of MICA, retrograde transport to the cytoplasm, and degradation by the proteasome. Our study identifies a novel strategy developed by melanoma cells to evade NK cell-mediated immune surveillance based on the intracellular sequestration of immature forms of MICA in the endoplasmic reticulum. Furthermore, this tumor immune escape strategy can be overcome by gene therapy approaches aimed at overexpressing MICA on tumor cells.
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1 This work was funded by grants from Agencia Nacional de Promoción Científica y Tecnológica, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Universidad de Buenos Aires, and Fundación Antorchas (all to N.W.Z.). M.B.F., M.V.G., and C.I.D. are postgraduate fellows of Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina. L.E.R. holds a fellowship of Agencia Nacional de Promoción Científica y Tecnológica. M.M.B. is a fellow of Fundación Sales. J.M., G.A.R., and N.W.Z. are members of the Researcher Career of Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina. Fundación Sales provided extra support.
2 Current address: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo de Investigaciones Científicas y Técnicas.
3 Current address: Department of Medicine, University of Chicago, Chicago, IL.
4 Address correspondence and reprint requests to Dr. Norberto W. Zwirner, Laboratorio de Inmunopatología., Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, C1428ADN Buenos Aires, Argentina. E-mail address: nwz{at}sinectis.com.ar
5 Abbreviations used in this paper: NKG2DL, NKG2D ligand; FC, flow cytometry; MICA/B, MHC class I chain-related gene A/B; sMICA, soluble MICA; ULBP, UL16-binding protein; ER, endoplasmic reticulum; IC, isotype-matched negative control mAb; LN, lymph node; DN, dominant negative; EGFP, enhanced GFP.
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