Dendritic cells (DCs) have a key role in regulating tumor immunity, tumor cell growth and drug resistance. We hypothesized that multiple myeloma (MM) cells might recruit and reprogram DCs to a tumor-permissive phenotype by changes within their microRNA (miRNA) network. By analyzing six different miRNA-profiling data sets, miR-29b was identified as the only miRNA upregulated in normal mature DCs and significantly downregulated in tumor-associated DCs. This finding was validated in primary DCs co-cultured in vitro with MM cell lines and in primary bone marrow DCs from MM patients. In DCs co-cultured with MM cells, enforced expression of miR-29b counteracted pro-inflammatory pathways, including signal transducer and activator of transcription 3 and nuclear factor-κB, and cytokine/chemokine signaling networks, which correlated with patients' adverse prognosis and development of bone disease. Moreover, miR-29b downregulated interleukin-23 in vitro and in the SCID-synth-hu in vivo model, and antagonized a Th17 inflammatory response. All together, these effects translated into strong anti-proliferative activity and reduction of genomic instability of MM cells. Our study demonstrates that MM reprograms the DCs functional phenotype by downregulating miR-29b whose reconstitution impairs DCs ability to sustain MM cell growth and survival. These results underscore miR-29b as an innovative and attractive candidate for miRNA-based immune therapy of MM.

中文翻译：

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MiR-29b拮抗多发性骨髓瘤培养的树突状细胞的促炎性肿瘤促进活性。

树突状细胞（DC）在调节肿瘤免疫力，肿瘤细胞生长和耐药性中起关键作用。我们假设多发性骨髓瘤（MM）细胞可能会通过其microRNA（miRNA）网络中的变化募集DC，并将DC重新编程为肿瘤允许的表型。通过分析六个不同的miRNA分析数据集，miR-29b被鉴定为在正常成熟DC中唯一被上调且在肿瘤相关DC中被显着下调的miRNA。这一发现在与MM细胞系体外共培养的原发DC和MM患者的原发性DC DC中得到了验证。在与MM细胞共培养的DC中，miR-29b的强制表达可抵制促炎途径，包括信号转导和转录激活因子3和核因子-κB以及与患者病情相关的细胞因子/趋化因子信号网络。骨骼疾病的不良预后和发展。此外，miR-29b在体外和SCID-synth-hu体内模型中均下调了白介素23，并拮抗Th17炎症反应。总之，这些作用转化为强大的抗增殖活性并降低了MM细胞的基因组不稳定性。我们的研究表明，MM通过下调miR-29b来重编程DC的功能表型，而miR-29b的重构会损害DC维持MM细胞生长和存活的能力。这些结果强调了miR-29b是基于MM的基于miRNA的免疫疗法的创新且有吸引力的候选药物。这些作用转化为强大的抗增殖活性，并降低了MM细胞的基因组不稳定性。我们的研究表明，MM通过下调miR-29b来重编程DC的功能表型，而miR-29b的重构会损害DC维持MM细胞生长和存活的能力。这些结果强调了miR-29b是基于MM的基于miRNA的免疫疗法的创新且有吸引力的候选药物。这些作用转化为强大的抗增殖活性，并降低了MM细胞的基因组不稳定性。我们的研究表明，MM通过下调miR-29b来重编程DC的功能表型，而miR-29b的重构会损害DC维持MM细胞生长和存活的能力。这些结果强调了miR-29b是基于MM的基于miRNA的免疫疗法的创新且有吸引力的候选药物。