title: Geldanamycin-mediated inhibition of heat shock protein 90 partially activates dendritic cells, but interferes with their full maturation, accompanied by impaired upregulation of RelB.
abstract: BACKGROUND
  The chaperon heat shock protein 90 (HSP90) constitutes an important target for anti-tumor therapy due to its essential role in the stabilization of oncogenes. However, HSP90 is ubiquitously active to orchestrate protein turnover, chemotherapeutics that target HSP90 may affect immune cells as a significant side effect. Therefore, we asked for potential effects of pharmacological HSP90 inhibition at a therapeutically relevant concentration on human dendritic cells (DCs) as main inducers of both cellular and humoral immune responses, and on human CD4⁺ T cells as directly activated by DCs and essential to confer B cell help.
  
  
  METHODS
  Unstimulated human monocyte-derived DCs (MO-DCs) were treated with the prototypical HSP90 inhibitor geldanamycin (GA). Based on dose titration studies performed to assess cytotoxic effects, GA was applied at a rather low concentration, comparable to serum levels of clinically used HSP90 inhibitors. The immuno-phenotype (surface markers, cytokines), migratory capacity, allo T cell stimulatory and polarizing properties (proliferation, cytokine pattern) of GA-treated MO-DCs were assessed. Moreover, effects of GA on resting and differentially stimulated CD4⁺ T cells in terms of cytotoxicity and proliferation were analysed.
  
  
  RESULTS
  GA induced partial activation of unstimulated MO-DCs. In contrast, when coapplied in the course of MO-DC stimulation, GA prevented the acquisition of a fully mature DC phenotype. Consequently, this MO-DC population exerted lower allo CD4⁺ T cell stimulation and cytokine production. Furthermore, GA exerted no cytotoxic effect on resting T cells, but abrogated proliferation of T cells stimulated by MO-DCs at either state of activation or by stimulatory antibodies.
  
  
  CONCLUSIONS
  HSP90 inhibitors at clinically relevant concentrations may modulate adaptive immune responses both on the level of DC activation and T cell proliferation. Surprisingly, unstimulated DCs may be partially activated by that agent. However, due to the potent detrimental effects of HSP90 inhibitors on stimulated CD4⁺ T cells, as an outcome a patients T cell responses might be impaired. Therefore, HSP90 inhibitors most probably are not suitable for treatment in combination with immunotherapeutic approaches aimed to induce DC/T cell activation.
authors: Stefanie
authors: S
authors: Trojandt
authors: Angelika B
authors: AB
authors: Reske-Kunz
authors: Department of Dermatology, Medical Center of the Johannes Gutenberg-University, Mainz, Germany. mbros@uni-mainz.de.
authors: Matthias
authors: M
authors: Bros
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008213:Lymphocyte Activation; D010641:Phenotype; D015398:Signal Transduction; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C497593:RELB protein, human; D051841:Transcription Factor RelB; C001277:geldanamycin