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

Abstract

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.

• Authors: Jumei Shi, Guido J Tricot, Tarun K Garg, Priyangi A Malaviarachchi, Susann M Szmania, Rachel E Kellum, Brian Storrie, Arend Mulder, John D Shaughnessy Jr, Bart Barlogie, Frits van Rhee
• Journal: Blood (Blood) Vol. 111 Issue 3 Pg. 1309-17 (Feb 01 2008) ISSN: 0006-4971 [Print] United States
• PMID: 17947507 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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