IIBBA   05544
INSTITUTO DE INVESTIGACIONES BIOQUIMICAS DE BUENOS AIRES
Unidad Ejecutora - UE
artículos
Título:
Intracellular Retention of the NKG2D Ligand MHC Class I Chain-Related Gene A in Human Melanomas Confers Immune Privilege and Prevents NK Cell-Mediated Cytotoxicity
Autor/es:
FUERTES MB, GIRART MV, MOLINERO LL, DOMAICA CI, ROSSI LE, BARRIO MM, MORDOH J, RABINOVICH GA, ZWIRNER NW
Revista:
JOURNAL OF IMMUNOLOGY
Editorial:
AmericanAssociation of Immunologists
Referencias:
Lugar: Baltimore, USA; Año: 2008 vol. 180 p. 4606 - 4614
ISSN:
0022-1767
Resumen:
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-gamma 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