title: 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.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Jumei
authors.initials: J
authors.lastname: Shi
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Tricot
authors.forename: Tarun K
authors.initials: TK
authors.lastname: Garg
authors.forename: Priyangi A
authors.initials: PA
authors.lastname: Malaviarachchi
authors.forename: Susann M
authors.initials: SM
authors.lastname: Szmania
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Kellum
authors.forename: Brian
authors.initials: B
authors.lastname: Storrie
authors.forename: Arend
authors.initials: A
authors.lastname: Mulder
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
mesh_terms: 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
chemical_list: D001897:Boronic Acids; D015395:Histocompatibility Antigens Class I; D061988:Proteasome Inhibitors; D011719:Pyrazines; D054340:Receptors, KIR; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex