Immunoproteasome down-modulation enhances the ability of dendritic cells to stimulate antitumor immunity.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Dannull, J; Lesher, D-T; Holzknecht, R; Qi, W; Hanna, G; Seigler, H; Tyler, DS; Pruitt, SK
Published Date
- December 15, 2007
Published In
Volume / Issue
- 110 / 13
Start / End Page
- 4341 - 4350
PubMed ID
- 17855630
International Standard Serial Number (ISSN)
- 0006-4971
Digital Object Identifier (DOI)
- 10.1182/blood-2007-04-083188
Language
- eng
Conference Location
- United States