Intracellular retention of the NKG2D ligand MICA in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity

FUERTES, MERCEDES BEATRIZ; GIRART, MARÍA VICTORIA; MOLINERO, LUCIANA LORENA; DOMAICA, CAROLINA INÉS; ROSSI, LUCAS EZEQUIEL; BARRIO, MARÍA MARCELA; MORDOH, JOSÉ; RABINOVICH, GABRIEL ADRIÁN; ZWIRNER, NORBERTO WALTER

JOURNAL OF IMMUNOLOGY

American Association of Immunology

Lugar: Bethesda; Año: 2008 vol. 180 p. 4606 - 4614

0022-1767

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-g 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 as 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 to 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 over-expressing MICA on tumor cells.