Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma
Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma
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DOI：
10.1172/jci98060
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发表时间：
2018-12-03
影响因子：
15.9
通讯作者：
Rivoltini, Licia
中科院分区：
文献类型：
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作者：
Huber, Veronica;Vallacchi, Viviana;Rivoltini, Licia
骨髓源性抑制细胞（MDSC）的积累是癌症患者有效免疫治疗的主要障碍，但在人类环境中这一过程的机制仍然难以捉摸。在此，我们描述了一组与MDSC相关的microRNA（miR-146 a、miR-155、miR-125 b、miR-100、let-7 e、miR-125 a、miR-146 b、miR-99 b），以及对黑色素瘤患者免疫检查点抑制剂治疗的耐药性。miR通过转录分析鉴定为负责由黑素瘤细胞外囊泡（EV）介导的单核细胞转化为MDSC（CD 14（+）HLA-DR阴性细胞），并且显示在转染后重建MDSC特征。在黑色素瘤患者中，这些miR在循环CD 14（+）单核细胞、血浆和肿瘤样本中增加，它们与髓样细胞浸润相关。在血浆中，其基线水平与CTLA-4或程序性细胞死亡蛋白1（PD-1）阻断的临床疗效相关。因此，MDSC相关miR代表癌症患者中MDSC活性的指标和不良免疫治疗结果的潜在血液标志物。
The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to effective immunotherapy in cancer patients, but the mechanisms underlying this process in the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14(+) HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs were increased in circulating CD14(+) monocytes, plasma, and tumor samples, where they correlated with the myeloid cell infiltrate. In plasma, their baseline levels clustered with the clinical efficacy of CTLA-4 or programmed cell death protein 1 (PD-1) blockade. Hence, MDSC-related miRs represent an indicator of MDSC activity in cancer patients and a potential blood marker of a poor immunotherapy outcome.