Journal
JOURNAL OF IMMUNOLOGY
Volume 176, Issue 8, Pages 4757-4765Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.176.8.4757
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Funding
- NCI NIH HHS [T32 CA75956, CA-16042, K12 CA76905, K23 CA93376, P50 CA086306, R01 CA77623, R01 CA79976] Funding Source: Medline
- NIAID NIH HHS [AI-28697] Funding Source: Medline
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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-kappa B nuclear transcription factor assay and gene-expression profiling of B16 treated with bortezomib was consistent with inhibition of NF-kappa B 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.
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