title: Heat shock protein-90 inhibitors increase MHC class I-related chain A and B ligand expression on multiple myeloma cells and their ability to trigger NK cell degranulation.
abstract: Modulation of the host immune system represents a promising therapeutic approach against cancer, including multiple myeloma. Recent findings indicate that the NK group 2D (NKG2D)- and DNAX accessory molecule-1 (DNAM-1)-activating receptors play a prominent role in tumor recognition and elimination by cytotoxic lymphocytes, suggesting that the levels of NKG2D and DNAM-1 ligand expression on tumor cells may be a critical factor to improve the immune response against cancer. In this study, we tested the effect of 17-allylaminogeldanamycin and radicicol, drugs targeting the heat shock protein-90 (HSP-90) chaperone protein and displaying antimyeloma activity, on the expression of NKG2D and DNAM-1 ligands in human myeloma cell lines. We demonstrate that HSP-90 inhibitors are able to up-regulate both MHC class I chain-related (MIC) A and MICB protein surface and mRNA expression in human myeloma cell lines, without any significant effect on the basal expression of the DNAM-1 ligand poliovirus receptor CD155, or induction of nectin-2 and UL16-binding proteins. Activation of the transcription factor heat shock factor-1 by HSP-90 inhibitors is essential for the up-regulation of MICA/MICB expression and knockdown of heat shock factor-1 using small hairpin RNA interference blocks this effect. Moreover, in vitro and in vivo binding of heat shock factor-1 to MICA and MICB promoters indicates that it may enhance NKG2D ligand expression at the transcriptional level. Finally, exposure to HSP-90 inhibitors renders myeloma cells more efficient to activate NK cell degranulation and a blocking Ab specific for NKG2D significantly reduces this effect. Thus, these results provide evidence that targeting NKG2D ligands expression may be an additional mechanism supporting the antimyeloma activity of HSP-90 inhibitors and suggest their possible immunotherapeutic value.
authors.affiliation: Department of Experimental Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome Sapienza, Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Fionda
authors.forename: Alessandra
authors.initials: A
authors.lastname: Soriani
authors.forename: Giulia
authors.initials: G
authors.lastname: Malgarini
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Iannitto
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
authors.forename: Marco
authors.initials: M
authors.lastname: Cippitelli
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology*; D045744:Cell Line, Tumor; D058851:GPI-Linked Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008024:Ligands; D009101:Multiple Myeloma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017510:Protein Folding / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*
chemical_list: D016227:Benzoquinones; D001897:Boronic Acids; D058851:GPI-Linked Proteins; D018841:HSP90 Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; D047029:Lactams, Macrocyclic; D008024:Ligands; C099187:MHC class I-related chain A; C098080:MICB antigen; D011719:Pyrazines; C423230:ULBP2 protein, human; C112765:tanespimycin; D000069286:Bortezomib