Natural Killer Cell Cytotoxicity Is Suppressed by Exposure to the Human NKG2D Ligand MICA*008 That Is Shed by Tumor Cells in Exosomes

Acknowledgments We 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.
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
Depto. de Biología Celular
Fac. de Ciencias Biológicas
TRUE
pub