Sensitization of tumor cells to NK cell-mediated killing by proteasome inhibition.
Bortezomib is a proteasome inhibitor that has direct antitumor effects. We and others have previously demonstrated that bortezomib could also sensitize tumor cells to killing via the death ligand, TRAIL. NK cells represent a potent antitumor effector cell. Therefore, we investigated whether bortezomib could sensitize tumor cells to NK cell-mediated killing. Preincubation of tumor cells with bortezomib had no effect on short-term NK cell killing or purified granule killing assays. Using a 24-h lysis assay, increases in tumor killing was only observed using perforin-deficient NK cells, and this increased killing was found to be dependent on both TRAIL and FasL, correlating with an increase in tumor Fas and DR5 expression. Long-term tumor outgrowth assays allowed for the detection of this increased tumor killing by activated NK cells following bortezomib treatment of the tumor. In a tumor purging assay, in which tumor:bone marrow cell mixtures were placed into lethally irradiated mice, only treatment of these mixtures with a combination of NK cells with bortezomib resulted in significant tumor-free survival of the recipients. These results demonstrate that bortezomib treatment can sensitize tumor cells to cellular effector pathways. These results suggest that the combination of proteasome inhibition with immune therapy may result in increased antitumor efficacy.
Hallett
William H D
WH
Department of Microbiology and Immunology, University of Nevada School of Medicine, University of Nevada, Reno, NV 89557, USA.
Ames
Erik
E
Motarjemi
Milad
M
Barao
Isabel
I
Shanker
Anil
A
Tamang
David L
DL
Sayers
Thomas J
TJ
Hudig
Dorothy
D
Murphy
William J
WJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein / Q000378:metabolism; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology*; D007938:Leukemia / Q000188:drug therapy / Q000628:therapy; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*; D054353:Perforin / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D053222:Fas Ligand Protein; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D054353:Perforin; D000069286:Bortezomib