Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma

Blood. 2008 Feb 1;111(3):1309-17. doi: 10.1182/blood-2007-03-078535. Epub 2007 Oct 18.


Human leukocyte antigen class I molecules expressed by tumor cells play a central role in the regulation of natural killer (NK) cell-mediated immune responses. The proteasome inhibitor bortezomib has demonstrated significant activity in multiple myeloma (MM). We hypothesized that treatment of MM with bortezomib results in the reduction of cell-surface expression of class I and thereby sensitizes MM to NK cell-mediated lysis. Here we report that bortezomib down-regulates class I in a time- and dose-dependent fashion on all MM cell lines and patient MM cells tested. Downregulation of class I can also be induced in vivo after a single dose of 1.0 mg/m(2) bortezomib. Bortezomib significantly enhances the sensitivity of patient myeloma to allogeneic and autologous NK cell-mediated lysis. Further, the level of decrease in class I expression correlates with increased susceptibility to lysis by NK cells. Clinically relevant bortezomib concentrations do not affect NK-cell function. Our findings have clear therapeutic implications for MM and other NK cell-sensitive malignancies in the context of both allogeneic and autologous adoptively transferred NK cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Boronic Acids / pharmacology*
  • Bortezomib
  • Cell Membrane / drug effects*
  • Cell Membrane / immunology
  • Cell Survival / drug effects
  • Down-Regulation / drug effects*
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / immunology*
  • Multiple Myeloma / immunology*
  • Multiple Myeloma / pathology
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Pyrazines / pharmacology*
  • Receptors, KIR / classification
  • Receptors, KIR / immunology
  • Sensitivity and Specificity
  • Tumor Cells, Cultured


  • Boronic Acids
  • Histocompatibility Antigens Class I
  • Proteasome Inhibitors
  • Pyrazines
  • Receptors, KIR
  • Bortezomib
  • Proteasome Endopeptidase Complex