Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma.
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.
Shi
Jumei
J
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Tricot
Guido J
GJ
Garg
Tarun K
TK
Malaviarachchi
Priyangi A
PA
Szmania
Susann M
SM
Kellum
Rachel E
RE
Storrie
Brian
B
Mulder
Arend
A
Shaughnessy
John D
JD
Barlogie
Bart
B
van Rhee
Frits
F
D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002462:Cell Membrane / Q000187:drug effects* / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D054340:Receptors, KIR / Q000145:classification / Q000276:immunology; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured
D001897:Boronic Acids; D015395:Histocompatibility Antigens Class I; D061988:Proteasome Inhibitors; D011719:Pyrazines; D054340:Receptors, KIR; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex