Immunosensitization of Tumor Cells to Dendritic Cell-activated Immune Responses with the Proteasome Inhibitor Bortezomib (Ps-341, Velcade).
From: Department of Surgery, Division of Surgical Oncology, University of California, Los Angeles 90095, USA.
Journal of immunology (Baltimore, Md. : 1950)
- Publish Date: Apr 2006
- ISSN: 0022-1767
- Volume: 176
- Issue: 8
- Pages: 4757-65
- Medium: Print
- Language: English
- Citation (JAMA): Schumacher Lana Y, Vo Dan D, Garban Hermes J, et al. Immunosensitization of Tumor Cells to Dendritic Cell-activated Immune Responses with the Proteasome Inhibitor Bortezomib (Ps-341, Velcade).. J. Immunol. Apr 2006;176:4757-65
Abstract
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.
Mesh Headings (Keywords): Animals, Apoptosis, Boronic Acids, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Cytotoxicity, Immunologic, Dendritic Cells, Immunization, Immunotherapy, Killer Cells, Natural, Melanoma, Experimental, Mice, Mice, Inbred C57BL, Mice, Knockout, Protease Inhibitors, Pyrazines, Tumor Necrosis Factor-alpha
Check for Full Text / PubMed Unique Identifier (PMID): 16585569
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