Immunosensitization of Tumor Cells to Dendritic Cell-Activated Immune Responses with the Proteasome Inhibitor Bortezomib (PS-341, Velcade)
| Autor: | Benjamin Bonavida, Dan D. Vo, Antoni Ribas, William H. McBride, James S. Economou, Vivian B. Dissette, Hermes Garban, Begoña Comin-Anduix, Lana Y. Schumacher, Sharla K. Owens, John A. Glaspy |
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| Rok vydání: | 2006 |
| Předmět: |
Cytotoxicity
Immunologic Immunology Melanoma Experimental Apoptosis CD8-Positive T-Lymphocytes In Vitro Techniques Bortezomib Mice Immune system Cell Line Tumor medicine Animals Immunology and Allergy Protease Inhibitors Cytotoxicity neoplasms Mice Knockout biology Tumor Necrosis Factor-alpha Effector Dendritic Cells Dendritic cell Boronic Acids Killer Cells Natural Mice Inbred C57BL Perforin Pyrazines Cancer cell Proteasome inhibitor Cancer research biology.protein Immunization Immunotherapy medicine.drug |
| Zdroj: | The Journal of Immunology. 176:4757-4765 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.176.8.4757 |
| Popis: | 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-κB nuclear transcription factor assay and gene-expression profiling of B16 treated with bortezomib was consistent with inhibition of NF-κB target genes leading to a proapoptotic phenotype. In vitro lytic assays demonstrated that TNF-α, 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. |
| Databáze: | OpenAIRE |
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