Geldanamycin-mediated inhibition of heat shock protein 90 partially activates dendritic cells,but interferes with their full maturation,accompanied by impaired upregulation of RelB

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. conclusion: 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. © 2014 trojandt et al.; licensee biomed central ltd.