Immunoproteasome down-modulation enhances the ability of dendritic cells to stimulate antitumor immunity.
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.
Dannull
Jens
J
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Lesher
Diem-Thu
DT
Holzknecht
Robert
R
Qi
Wenning
W
Hanna
Gabi
G
Seigler
Hilliard
H
Tyler
Douglas S
DS
Pruitt
Scott K
SK
D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000235:genetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
D000951:Antigens, Neoplasm; D034741:RNA, Small Interfering; D046988:Proteasome Endopeptidase Complex