Differential Response of Myeloid-Derived Suppressor Cells to the Nonsteroidal Anti-Inflammatory Agent Indomethacin in Tumor-Associated and Tumor-Free Microenvironments

髓源性抑制细胞 肿瘤微环境 癌症研究 炎症 免疫系统 免疫学 背景(考古学) CD8型 药理学 医学 生物 抑制器 癌症 内科学 古生物学
作者
Ada G. Blidner,Mariana Salatino,Iván Mascanfroni,Miriam Diament,Elisa Bal de Kier Joffé,María A. Jasnis,Slobodanka Klein,Gabriel A. Rabinovich
出处
期刊:Journal of Immunology [American Association of Immunologists]
卷期号:194 (7): 3452-3462 被引量:31
标识
DOI:10.4049/jimmunol.1401144
摘要

Abstract Myeloid-derived suppressor cells (MDSCs) are key regulatory cells that control inflammation and promote tumor-immune escape. To date, no specific immunomodulatory drug has proven efficacy in targeting the expansion and/or function of these cells in different pathophysiologic settings. In this study, we identified a context-dependent effect of the nonsteroidal anti-inflammatory drug indomethacin (IND) on MDSCs, depending on whether they were derived from tumor microenvironments (TME) or from tumor-free microenvironments (TFME). Treatment of mice bearing the LP07 lung adenocarcinoma with IND inhibited the suppressive activity of splenic MDSCs, which restrained tumor growth through mechanisms involving CD8+ T cells. The same effect was observed when MDSCs were treated with IND and conditioned media from LP07 tumor cells in vitro. However, in the absence of a tumor context, IND enhanced the intrinsic suppressive function of MDSCs and amplified their protumoral activity. In a model of autoimmune neuroinflammation, IND-treated MDSCs differentiated in TFME attenuated inflammation, whereas IND-treated MDSCs differentiated in TME aggravated clinical symptoms and delayed resolution of the disease. Mechanistically, IND reduced arginase activity as well as NO and reactive oxygen species production in MDSCs differentiated in TME but not in TFME. Moreover, expression of the C/EBP-β transcription factor isoforms correlated with the suppressive activity of IND-treated MDSCs. Our study unveils the dual and context-dependent action of IND, a drug that serves both as an anti-inflammatory and anticancer agent, which differentially affects MDSC activity whether these cells are derived from TME or TFME. These results have broad clinical implication in cancer, chronic inflammation and autoimmunity.
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