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* Department of Experimental Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome Sapienza, Rome, Italy; and
Regina Elena Cancer Institute, Rome, Italy
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.
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 This work was partially supported by grants from the Italian Association for Cancer Research, the Italian Ministry of University and Research, and the Italian Ministry of Public Health, Progetti di Ricerca di Interesse Nazionale and Fondo per gli Investimenti alla Ricerca di Base Projects.
2 A.S. and M.C. contributed equally to this paper.
3 Address correspondence and reprint requests to Dr. Angela Santoni or Dr. Marco Cippitelli, Department of Experimental Medicine, University La Sapienza, Viale Regina Elena 324, 00161 Rome, Italy. E-mail address: angela.santoni{at}uniroma1.it or marco.cippitelli{at}uniroma1.it
4 Abbreviations used in this paper: MM, multiple myeloma; 17-AAG, 17-allylamino-17-demethoxygeldanamycin; DNAM-1, DNAX accessory molecule-1; HSF-1, heat shock factor-1; HSR, heat shock response; TM, tunicamycin; TG, thapsigargin; NEC-2, nectin-2; PVR, poliovirus receptor CD155; UPR, unfolded protein response; XBP-1, X-box-binding protein-1; MIC, MHC class I chain-related; HSE, HS response element; ChIP, chromatin immunoprecipitation assay; ER, endoplasmic reticulum; CHOP, C/EBP homologous protein; shRNA, small hairpin RNA; NKG2D, NK group 2D.
5 The online version of this article contains supplemental material.
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