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

Jens Dannull, Diem Thu Lesher, Robert Holzknecht, Wenning Qi, Gabi Hanna, Hilliard Seigler, Douglas S. Tyler, Scott K. Pruitt

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

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 transfected 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 antitumor immune responses, may lead to more effective DC-based tumor immunotherapy.

Original languageEnglish (US)
Pages (from-to)4341-4350
Number of pages10
JournalBlood
Volume110
Issue number13
DOIs
StatePublished - Dec 15 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Dannull, J., Lesher, D. T., Holzknecht, R., Qi, W., Hanna, G., Seigler, H., Tyler, D. S., & Pruitt, S. K. (2007). Immunoproteasome down-modulation enhances the ability of dendritic cells to stimulate antitumor immunity. Blood, 110(13), 4341-4350. https://doi.org/10.1182/blood-2007-04-083188