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
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
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DOI：
10.4049/jimmunol.0901797
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发表时间：
2009-10-01
影响因子：
4.4
通讯作者：
Cippitelli, Marco
中科院分区：
文献类型：
--
作者：
Fionda, Cinzia;Soriani, Alessandra;Cippitelli, Marco
调节宿主免疫系统代表了一种有前景的针对癌症（包括多发性骨髓瘤）的治疗方法。最近的研究结果表明，NK组2D（NKG 2D）和DNAX辅助分子-1（DNAM-1）激活受体在细胞毒性淋巴细胞识别和消除肿瘤中起着重要作用，这表明肿瘤细胞上NKG 2D和DNAM-1配体的表达水平可能是改善抗癌免疫反应的关键因素。在这项研究中，我们测试了17-烯丙基氨基格尔德霉素和根赤霉素，靶向热休克蛋白-90（HSP-90）伴侣蛋白和显示抗骨髓瘤活性的药物，对人骨髓瘤细胞系中NKG 2D和DNAM-1配体表达的影响。我们证明，HSP-90抑制剂能够上调人类骨髓瘤细胞系中MHC I类链相关（MIC）A和MICB蛋白表面和mRNA表达，而对DNAM-1配体脊髓灰质炎病毒受体CD 155的基础表达无任何显著影响，或诱导nectin-2和UL 16结合蛋白。HSP-90抑制剂对转录因子热休克因子-1的激活对于云母/MICB表达的上调是必不可少的，并且使用小发夹RNA干扰阻断热休克因子-1的敲低（knockdown）这种作用。此外，在体外和体内结合的热休克因子-1云母和MICB启动子表明，它可以提高NKG 2D配体的表达在转录水平。最后，暴露于HSP-90抑制剂使骨髓瘤细胞更有效地激活NK细胞脱粒，而NKG 2D特异性阻断性Ab可显著降低该效应。因此，这些结果提供了证据，靶向NKG 2D配体表达可能是支持HSP-90抑制剂抗骨髓瘤活性的额外机制，并表明其可能的免疫学价值。免疫学杂志，2009，183：4385-4394.
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 Journal of Immunology, 2009, 183: 4385-4394.