TY - JOUR
T1 - Immunoproteasome down-modulation enhances the ability of dendritic cells to stimulate antitumor immunity
AU - Dannull, Jens
AU - Lesher, Diem Thu
AU - Holzknecht, Robert
AU - Qi, Wenning
AU - Hanna, Gabi
AU - Seigler, Hilliard
AU - Tyler, Douglas S.
AU - Pruitt, Scott K.
PY - 2007/12/15
Y1 - 2007/12/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=39649085607&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=39649085607&partnerID=8YFLogxK
U2 - 10.1182/blood-2007-04-083188
DO - 10.1182/blood-2007-04-083188
M3 - Article
C2 - 17855630
AN - SCOPUS:39649085607
SN - 0006-4971
VL - 110
SP - 4341
EP - 4350
JO - Blood
JF - Blood
IS - 13
ER -