Intracellular retention of MICA in melanoma prevents recognition by NK cells: novel tumor-immune escape mechanism?

MERCEDES FUERTES, LUCIANA MOLINERO, MARÍA V. GIRART, CAROLINA DOMAICA, MARCELA BARRIO, JOSÉ MORDOH, GABRIEL A. RABINOVICH, NORBERTO ZWIRNER

San Diego, USA

Congreso; American Association of Immunologists Annual Meeting; 2005

American Association of Immunologists

Intracellular retention of MICA in melanomas prevents recognition by NK cells: novel tumor immune escape mechanism   Mercedes Beatriz Fuertes, Luciana Lorena Molinero, María Victoria Girart, Carolina Inés Domaica, Marcela Barrio, José Mordoh, Gabriel Adrián Rabinovich and Norberto Walter Zwirner   Most tumors express MICA/B and ULBP-1/-3, ligands for the NKG2D cytotoxicity activating receptor, but grow in competent hosts. Our aim was to elucidate novel strategies developed by melanomas to resist NK cell cytotoxicity. By flow cytometry, 5/11 human melanoma cell lines did not express MICA and expressed only one ULBP. However, MICA was detected by Western blot and immunofluorescence on permeabilized cells. A pool of MICA in the ER and Golgi apparatus, but not in endosomes/lysosomes, was detected by confocal microscopy. No secreted MICA was detected by ELISA. MEL-LES, a melanoma with low surface MICA resisted NK cell cytotoxicity. Three clones (1C1, 1C10 and 2A2) with high levels of surface MICA were produced by transfection with full length MICA. They grew in vitro (MTS assay) at identical rates as a clone transfected with empty plasmid (F3). In vivo tumor growth in nude mice showed that at day 53, the tumor free mice were: F3: 27%, 1C1: 100%, 1C10: 80%, 2A2: 100%. Hence, some melanomas retain MICA in intracellular compartments and prevent its surface expression to avoid NK cell cytotoxicity. Induction of surface MICA elicits a NK cell cytotoxic response that delays in vivo tumor growth. This mechanism may constitute a novel tumor immune escape mechanism with implications in the design of anti-tumor immunotherapies. Support: ANPCyT, UBA and Fund. Antorchas.