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Immunosensitization of Tumor Cells to Dendritic Cell-Activated Immune Responses with the Proteasome Inhibitor Bortezomib (PS-341, Velcade)¹

Lana Y. Schumacher^*,||, Dan D. Vo^*, Hermes J. Garban^*, Begoña Comin-Anduix^*, Sharla K. Owens^*,||, Vivian B. Dissette^*, John A. Glaspy, William H. McBride^,, Benjamin Bonavida^,¶, James S. Economou^*,,¶ and Antoni Ribas^2,*,,

^* Department of Surgery, Division of Surgical Oncology, Department of Medicine, Division of Hematology-Oncology, Department of Experimental Radiation Oncology, Jonsson Comprehensive Cancer Center, and ^¶ Departments of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095; and ^|| Department of Surgery, Stanford University Hospital, Stanford, CA 94305

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-B nuclear transcription factor assay and gene-expression profiling of B16 treated with bortezomib was consistent with inhibition of NF-B target genes leading to a proapoptotic phenotype. In vitro lytic assays demonstrated that TNF-, 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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