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Phenotypic and Functional Effects of Heat Shock Protein 90 Inhibition on Dendritic Cell

Jooeun Bae^*,, Constantine Mitsiades^*, Yu-Tzu Tai^*, Robert Bertheau^*,, Masood Shammas^*,, Ramesh Babu Batchu^*,, Cheng Li^*, Lawrence Catley^*, Rao Prabhala^*,, Kenneth C. Anderson^* and Nikhil C. Munshi^1,*,

^* Dana-Farber Cancer Institute and Veterans Affairs Boston Healthcare System, Harvard Medical School, Boston, MA 02115

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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Nikhil C. Munshi, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. E-mail address: nikhil_munshi{at}dfci.harvard.edu

² Abbreviations used in this paper: Hsp90, 90-kDa heat shock protein; DC, dendritic cell; immDC, immature DC; mDC, mature DC; MFI, mean fluorescence intensity.