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

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 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.

journal_name

Blood

journal_title

Blood

authors

Dannull J,Lesher DT,Holzknecht R,Qi W,Hanna G,Seigler H,Tyler DS,Pruitt SK

doi

10.1182/blood-2007-04-083188

subject

Has Abstract

pub_date

2007-12-15 00:00:00

pages

4341-50

issue

13

eissn

0006-4971

issn

1528-0020

pii

blood-2007-04-083188

journal_volume

110

pub_type

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