RT Journal Article
T1 Natural Killer Cell Cytotoxicity Is Suppressed by Exposure to the Human NKG2D Ligand MICA*008 That Is Shed by Tumor Cells in Exosomes
A1 Ashiru, Omodele
A1 Boutet, Philippe
A1 Fernández Messina, Lola María
A1 Agüera-González, Sonia
A1 Skepper, Jeremy
A1 Valés-Gómez, Mar
A1 Reyburn, Hugh
AB The MHC class I–related chain (MIC) A and MICB ligands for the activating receptor NKG2D can be shed from tumor cells, and the presence of these soluble molecules in sera is related with compromised immune response and progression of disease. Recently, thiol disulphide isomerases and members of the ADAM (a disintegrin and metalloproteinase) gene family were identified as key enzymes in mediating MICA/B shedding from cells. Here, we report shedding of the most frequently expressed MICA allele in human populations (MICA*008) into exosomes, small membrane vesicles that are secreted upon fusion with the plasma membrane. Although similar to other MICA/B molecules in the extracellular domain, the predicted transmembrane and cytoplasmic domains of MICA*008 are quite different, and this difference seemed to be critical for the mode of release from tumor cells. Treatment of natural killer (NK) cells with exosomes containing MICA*008 molecules not only triggered downregulation of NKG2D from the cell surface but also provoked a marked reduction in NK cytotoxicity that is independent of NKG2D ligand expression by the target cell. Our findings reveal a mechanism of NK suppression in cancer that may facilitate immune escape and progression. Cancer Res; 70(2); 481–9
PB American Association for Cancer Research
SN 0008-5472
YR 2010
FD 2010
LK https://hdl.handle.net/20.500.14352/97201
UL https://hdl.handle.net/20.500.14352/97201
LA eng
NO Omodele Ashiru, Philippe Boutet, Lola Fernández-Messina, Sonia Agüera-González, Jeremy N. Skepper, Mar Valés-Gómez, Hugh T. Reyburn; Natural Killer Cell Cytotoxicity Is Suppressed by Exposure to the Human NKG2D Ligand MICA*008 That Is Shed by Tumor Cells in Exosomes. Cancer Res 15 January 2010; 70 (2): 481–489. https://doi.org/10.1158/0008-5472.CAN-09-1688
NO AcknowledgmentsWe thank S.J. Powis (University of St. Andrews), P. Roda-Navarro, Dr. F. Colucci and his group, and Dr. A. Kelly for helpful discussions; Prof. J. Trowsdale for critical reading of the manuscript; and N. Miller for assistance with cell sorting.Grant Support: Medical Research Council and Leukemia Research Fund. M. Valés-Gómez is a recipient of a New Investigator Award Grant from the Medical Research Council. O. Ashiru and P. Boutet were partially supported by The Newton Trust. S. Agüera-González was supported by Fundacion Caja Madrid and Ibercaja.
NO Medical Research Council (UK)
NO Leukemia Research Fund
NO The Isaac Newton Trust
NO Fundación Caja Madrid
NO Ibercaja
DS Docta Complutense
RD 6 abr 2025