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 Tyler, Scott K. Pruitt

Research output: Contribution to journalArticle

52 Citations (Scopus)

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

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Proteasome Endopeptidase Complex
Dendritic Cells
Immunity
Modulation
Tumors
T-cells
Cytotoxic T-Lymphocytes
Immunotherapy
Small Interfering RNA
Melanoma
Melanoma-Specific Antigens
Antigens
Neoplasms
Peptides
Transfection
Monocytes
Cells
RNA
Chemical analysis

ASJC Scopus subject areas

  • Hematology

Cite this

Dannull, J., Lesher, D. T., Holzknecht, R., Qi, W., Hanna, G., Seigler, H., ... 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

Immunoproteasome down-modulation enhances the ability of dendritic cells to stimulate antitumor immunity. / Dannull, Jens; Lesher, Diem Thu; Holzknecht, Robert; Qi, Wenning; Hanna, Gabi; Seigler, Hilliard; Tyler, Douglas; Pruitt, Scott K.

In: Blood, Vol. 110, No. 13, 15.12.2007, p. 4341-4350.

Research output: Contribution to journalArticle

Dannull, J, Lesher, DT, Holzknecht, R, Qi, W, Hanna, G, Seigler, H, Tyler, D & Pruitt, SK 2007, 'Immunoproteasome down-modulation enhances the ability of dendritic cells to stimulate antitumor immunity', Blood, vol. 110, no. 13, pp. 4341-4350. https://doi.org/10.1182/blood-2007-04-083188
Dannull J, Lesher DT, Holzknecht R, Qi W, Hanna G, Seigler H et al. Immunoproteasome down-modulation enhances the ability of dendritic cells to stimulate antitumor immunity. Blood. 2007 Dec 15;110(13):4341-4350. https://doi.org/10.1182/blood-2007-04-083188
Dannull, Jens ; Lesher, Diem Thu ; Holzknecht, Robert ; Qi, Wenning ; Hanna, Gabi ; Seigler, Hilliard ; Tyler, Douglas ; Pruitt, Scott K. / Immunoproteasome down-modulation enhances the ability of dendritic cells to stimulate antitumor immunity. In: Blood. 2007 ; Vol. 110, No. 13. pp. 4341-4350.
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