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

Published

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

Pubmed Central 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