Submitted April 4, 2007
Accepted August 31, 2007
Immunoproteasome down-modulation enhances the ability of dendritic cells to stimulate anti-tumor immunity
Jens Dannull, Diem-Thu Lesher, Robert Holzknecht, Wenning Qi, Gabi Hanna, Hilliard Seigler, Douglas S Tyler, and Scott K. Pruitt*
Department of Surgery, Duke University Medical Center, Durham, NC, United States
Department of Surgery, Durham VA Medical Center, Durham, NC, United States
* Corresponding author; email: scott.pruitt{at}duke.edu.
The process of dendritic cell (DC) maturation, critical for effective DC-based immunotherapy, also alters the proteasome such that peptides presented in the context of HLA class I are generated not by the constitutive proteasome, but by the immunoproteasome. CTL induced by such DC might not optimally recognize tumor cells normally expressing the constitutive proteasome. Using siRNA transfection of DC to inhibit expression of the three inducible immunoproteasome subunits in mature DC, we found that such DC expressed increased intracellular levels of constitutive proteasomes and presented an altered repertoire of tumor antigenic peptides. When DC generated from monocytes of three melanoma patients were transfected with immunoproteasome siRNA, induced to mature, and then transfected with RNA encoding defined melanoma antigens, these DC were superior inducers of antigen-specific CTL against autologous melanoma cells. This alteration of DC proteasome composition, which enhances the ability of mature antigen-loaded DC to stimulate anti-tumor immune responses, may lead to more effective DC-based tumor immunotherapy.
