Immunosensitization of tumor cells to dendritic cell-activated immune responses with the proteasome inhibitor bortezomib (PS-341, Velcade).
Proteasome inhibition results in proapoptotic changes in cancer cells, which may make them more sensitive to immune effector cells. We established a murine model to test whether the proteasome inhibitor bortezomib could sensitize established B16 melanoma tumors to dendritic cell (DC)-activated immune effector cells. Day 3-established s.c. B16 tumors had significantly decreased tumor outgrowth when treated with a combination of bortezomib and DC, regardless of whether the DC were loaded or not with a tumor Ag. In vivo Ab-depletion studies demonstrated that the effector cells were NK and CD8+ cells, but not CD4+ cells. NF-kappaB nuclear transcription factor assay and gene-expression profiling of B16 treated with bortezomib was consistent with inhibition of NF-kappaB target genes leading to a proapoptotic phenotype. In vitro lytic assays demonstrated that TNF-alpha, but not perforin, Fas-ligand, or TRAIL, was responsible for bortezomib-sensitized B16 cytotoxicity. In conclusion, the proteasome inhibitor bortezomib can pharmacologically sensitize tumor cells to the lytic effects of DC-activated immune effector cells.
Department of Surgery, Division of Surgical Oncology, University of California, Los Angeles 90095, USA.
Lana Y
LY
Schumacher
Dan D
DD
Vo
Hermes J
HJ
Garban
Begoña
B
Comin-Anduix
Sharla K
SK
Owens
Vivian B
VB
Dissette
John A
JA
Glaspy
William H
WH
McBride
Benjamin
B
Bonavida
James S
JS
Economou
Antoni
A
Ribas
D000818:Animals; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D007114:Immunization; D007167:Immunotherapy; D066298:In Vitro Techniques; D007694:Killer Cells, Natural / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib