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MicroRNAs in Tumor Exosomes Drive Immune Escape in Melanoma.
Cancer Immunology Research ( IF 10.1 ) Pub Date : 2019-12-19 , DOI: 10.1158/2326-6066.cir-19-0522
Virginie Vignard 1, 2, 3 , Maureen Labbé 1, 3 , Nadège Marec 4 , Gwennan André-Grégoire 5, 6 , Nicolas Jouand 4 , Jean-François Fonteneau 1, 3 , Nathalie Labarrière 1, 3 , Delphine Fradin 1, 3, 7
Affiliation  

MicroRNAs (miRNA), small noncoding RNAs that regulate gene expression, exist not only in cells but also in a variety of body fluids. These circulating miRNAs could enable intercellular communication. miRNAs are packaged in membrane-encapsulated vesicles, such as exosomes, or protected by RNA-binding proteins. Here, we report that miRNAs included in human melanoma exosomes regulate the tumor immune response. Using microscopy and flow cytometry, we demonstrate that CD8+ T cells internalize exosomes from different tumor types even if these cells do not internalize vesicles as readily as other immune cells. We explored the function of melanoma-derived exosomes in CD8+ T cells and showed that these exosomes downregulate T-cell responses through decreased T-cell receptor (TCR) signaling and diminished cytokine and granzyme B secretions. The result reduces the cells' cytotoxic activity. Using mimics, we found that miRNAs enriched in exosomes-such as Homo sapiens (hsa)-miR-3187-3p, hsa-miR-498, hsa-miR-122, hsa-miR149, and hsa-miR-181a/b-regulate TCR signaling and TNFα secretion. Our observations suggest that miRNAs in melanoma-derived exosomes aid tumor immune evasion and could be a therapeutic target.

中文翻译:

肿瘤外泌体中的MicroRNA驱动黑色素瘤的免疫逃逸。

MicroRNA(miRNA)是调节基因表达的小型非编码RNA,不仅存在于细胞中,而且还存在于多种体液中。这些循环的miRNA可以实现细胞间通讯。miRNA被包装在膜包裹的囊泡(如外来体)中,或被RNA结合蛋白保护。在这里,我们报道了人类黑色素瘤外泌体中包含的miRNA调节肿瘤的免疫反应。使用显微镜和流式细胞仪,我们证明CD8 + T细胞内化来自不同肿瘤类型的外泌体,即使这些细胞不像其他免疫细胞一样容易内化囊泡。我们探讨了黑色素瘤来源的外泌体在CD8 + T细胞中的功能,并显示这些外泌体通过减少T细胞受体(TCR)信号传导并减少细胞因子和粒酶B分泌来下调T细胞反应。结果降低了细胞的细胞毒性活性。使用模拟物,我们发现富含外泌体的miRNA,例如智人(hsa)-miR-3187-3p,hsa-miR-498,hsa-miR-122,hsa-miR149和hsa-miR-181a / b-调节TCR信号和TNFα分泌。我们的观察结果表明,黑色素瘤来源的外来体中的miRNA有助于逃避肿瘤,可能是治疗靶点。
更新日期:2020-02-03
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