MicroRNA-155 Expression Is Enhanced by T-cell Receptor Stimulation Strength and Correlates with Improved Tumor Control in Melanoma
MicroRNA-155 Expression Is Enhanced by T-cell Receptor Stimulation Strength and Correlates with Improved Tumor Control in Melanoma
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DOI：
10.1158/2326-6066.cir-18-0504
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发表时间：
2019-06-01
影响因子：
10.1
通讯作者：
Romero, Pedro
中科院分区：
文献类型：
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作者：
Martinez-Usatorre, Amaia;Sempere, Lorenzo F.;Romero, Pedro
microRNA是短的非编码RNA，在转录后调节蛋白质表达。我们先前发现miR-155促进效应CD 8（+）T细胞应答。然而，关于miR-155表达的调控知之甚少。在这里，我们报告了抗原亲和力和剂量决定了miR-155在CD 8（+）T细胞中的表达。在表达低亲和力抗原配体的B16肿瘤中，肿瘤特异性浸润性CD 8（+）T细胞显示出可变的miR-155表达，而高miR-155表达与更多的精氨酸产生细胞和肿瘤控制相关。此外，抗PD-1治疗导致miR-155表达增加和特异性CD 8（+）T细胞对肿瘤的控制。此外，在LCMV cl 13慢性病毒感染模型中，miR-155过表达增强了耗竭的CD 8（+）T细胞的持久性。与小鼠模型中的这些观察结果一致，人效应记忆CD 8（+）T细胞中的miR-155表达与其在黑色素瘤患者肿瘤浸润淋巴结中的频率呈正相关。肿瘤中的低miR-155靶基因签名与黑色素瘤患者的总生存期延长相关。总之，这些结果提高了在CD 8（+）肿瘤浸润性T细胞中高miR-155表达可能是原位抗原特异性CD 8（+）T细胞应答的相对效力的替代标志物的可能性。
microRNAs are short noncoding RNAs that regulate protein expression posttranscriptionally. We previously showed that miR-155 promotes effector CD8(+) T-cell responses. However, little is known about the regulation of miR-155 expression. Here, we report that antigen affinity and dose determine miR-155 expression in CD8(+) T cells. In B16 tumors expressing a low-affinity antigen ligand, tumor-specific infiltrating CD8(+) T cells showed variable miR-155 expression, whereby high miR-155 expression was associated with more cytokine-producing cells and tumor control. Moreover, anti-PD-1 treatment led to both increased miR-155 expression and tumor control by specific CD8(+) T cells. In addition, miR-155 overexpression enhanced exhausted CD8(+) T-cell persistence in the LCMV cl13 chronic viral infection model. In agreement with these observations in mouse models, miR-155 expression in human effector memory CD8(+) T cells positively correlated with their frequencies in tumor-infiltrated lymph nodes of melanoma patients. Low miR-155 target gene signature in tumors was associated with prolonged overall survival in melanoma patients. Altogether, these results raise the possibility that high miR-155 expression in CD8(+) tumor-infiltrating T cells may be a surrogate marker of the relative potency of in situ antigen-specific CD8(+) T-cell responses.