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 Blood, 15 December 2007, Vol. 110, No. 13, pp. 4341-4350.
Prepublished online as a Blood First Edition Paper on September 12, 2007; DOI 10.1182/blood-2007-04-083188.

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IMMUNOBIOLOGY

Immunoproteasome down-modulation enhances the ability of dendritic cells to stimulate antitumor immunity

Jens Dannull1, Diem-Thu Lesher1, Robert Holzknecht2, Wenning Qi1, Gabi Hanna1, Hilliard Seigler1,2, Douglas S. Tyler1,2, and Scott K. Pruitt1,2

1 Department of Surgery, Duke University Medical Center, Durham; and 2 Department of Surgery, Durham Veterans Administration Medical Center, NC

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. Cytotoxic T lymphocytes (CTLs) induced by such DCs might not optimally recognize tumor cells normally expressing the constitutive proteasome. Using small interfering RNA (siRNA) transfection of DCs to inhibit expression of the 3 inducible immunoproteasome subunits in mature DCs, we found that such DCs expressed increased intracellular levels of constitutive proteasomes and presented an altered repertoire of tumor-antigenic peptides. When DCs generated from the monocytes of 3 patients with melanoma were transfected with immunoproteasome siRNA, induced to mature, and then trans-fected with RNA encoding defined melanoma antigens, these DCs were superior inducers of antigen-specific CTLs against autologous melanoma cells. This alteration of DC proteasome composition, which enhances the ability of mature antigen-loaded DCs to stimulate anti-tumor immune responses, may lead to more effective DC-based tumor immunotherapy.


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