TUMOR IMMUNE ESCAPE BASED ON RETENTION OF THE NKG2D LIGAND MICA IN THE ENDOPLASMIC RETICULUM.

MERCEDES BEATRIZ FUERTES; MARÍA VICTORIA GIRART; CAROLINA INÉS DOMAICA; MARCELA BARRIO; JOSÉ MORDOH; GABRIEL ADRIÁN RABINOVICH; NORBERTO WALTER ZWIRNER

Córdoba, Argentina

Congreso; VII Congreso Latinoamericano de Inmunología.; 2005

Asociación Latinoamericana de Inmunología

Most tumors express MICA/B, ligands for the NKG2D cytotoxicity activating receptor, but grow in competent hosts. Previously we demonstrated that 5/10 human melanoma cell lines express MICA but avoid its exposition on the cell surface. Transfection of the IIB-Mel-LES human melanoma cell line with MICA restored surface expression resulting in an enhanced in vitro NK cell mediated cytotoxicity and IFN-g secretion, and delayed in vivo growth in nude mice. Here, we demonstrated by flow cytometry and Western Blot analysis that this intracellular retention was mirrored in 2/5 human metastasis of freshly isolated melanomas. Furthermore, performing colocalization experiments and confocal microscopy we detected that MICA was mostly retained in the endoplasmic reticulum (ER) but not in the Golgi apparatus, late endosomes/lysosomes or early endosomes in different melanoma cell lines. Finally, performing TUNEL assays we observed that the delay in the in vivo growth of the MICA-overexpressing clones was due to an enhanced in vivo apoptosis most likely induced by NK cells. Hence, intracellular retention of MICA in the ER constitutes a novel tumor immune escape mechanism also operative in freshly isolated melanomas.