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: Cinzia Fionda, Alessandra Soriani, Giulia Malgarini, Maria Luisa Iannitto, Angela Santoni, Marco Cippitelli
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 183 Issue 7 Pg. 4385-94 (Oct 01 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 19748980 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoquinones
• Boronic Acids
• GPI-Linked Proteins
• HSP90 Heat-Shock Proteins
• Histocompatibility Antigens Class I
• Intercellular Signaling Peptides and Proteins
• Lactams, Macrocyclic
• Ligands
• MHC class I-related chain A
• MICB antigen
• Pyrazines
• ULBP2 protein, human
• tanespimycin
• Bortezomib

Topics

• Benzoquinones (pharmacology)
• Boronic Acids (pharmacology)
• Bortezomib
• Cell Degranulation (drug effects, immunology)
• Cell Line, Tumor
• GPI-Linked Proteins
• Gene Expression Regulation, Neoplastic (drug effects)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Histocompatibility Antigens Class I (biosynthesis, immunology, metabolism)
• Humans
• Intercellular Signaling Peptides and Proteins (biosynthesis, genetics, metabolism)
• Killer Cells, Natural (immunology, metabolism, pathology)
• Lactams, Macrocyclic (pharmacology)
• Ligands
• Multiple Myeloma (immunology, metabolism, pathology)
• Protein Folding (drug effects)
• Pyrazines (pharmacology)
• Up-Regulation (drug effects, immunology)