Phenotypic and functional effects of heat shock protein 90 inhibition on dendritic cell.
The 90-kDa heat shock protein (Hsp90) plays an important role in conformational regulation of cellular proteins and thereby cellular signaling and function. As Hsp90 is considered a key component of immune function and its inhibition has become an important target for cancer therapy, we here evaluated the role of Hsp90 in human dendritic cell (DC) phenotype and function. Hsp90 inhibition significantly decreased cell surface expression of costimulatory (CD40, CD80, CD86), maturation (CD83), and MHC (HLA-A, B, C and HLA-DP, DQ, DR) markers in immature DC and mature DC and was associated with down-regulation of both RNA and intracellular protein expression. Importantly, Hsp90 inhibition significantly inhibited DC function. It decreased Ag uptake, processing, and presentation by immature DC, leading to reduced T cell proliferation in response to tetanus toxoid as a recall Ag. It also decreased the ability of mature DC to present Ag to T cells and secrete IL-12 as well as induce IFN-gamma secretion by allogeneic T cells. These data therefore demonstrate that Hsp90-mediated protein folding is required for DC function and, conversely, Hsp90 inhibition disrupts the DC function of significant relevance in the setting of clinical trials evaluating novel Hsp90 inhibitor therapy in cancer.
Bae
Jooeun
J
Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Mitsiades
Constantine
C
Tai
Yu-Tzu
YT
Bertheau
Robert
R
Shammas
Masood
M
Batchu
Ramesh Babu
RB
Li
Cheng
C
Catley
Lawrence
L
Prabhala
Rao
R
Anderson
Kenneth C
KC
Munshi
Nikhil C
NC
D017951:Antigen Presentation; D000941:Antigens / Q000378:metabolism; D000954:Antigens, Surface / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000737:chemistry / Q000187:drug effects / Q000276:immunology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology; D013745:Tetanus Toxoid / Q000494:pharmacology
D000941:Antigens; D000954:Antigens, Surface; D018841:HSP90 Heat-Shock Proteins; D013745:Tetanus Toxoid