miR-149-3p reverses CD8+ T-cell exhaustion by reducing inhibitory receptors and promoting cytokine secretion in breast cancer cells
miR-149-3p reverses CD8+ T-cell exhaustion by reducing inhibitory receptors and promoting cytokine secretion in breast cancer cells
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miR-149-3p通过减少乳腺癌细胞中的抑制性受体并促进细胞因子分泌来逆转CD8 T细胞耗竭
DOI：
10.1098/rsob.190061
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发表时间：
2019-10-01
期刊：
影响因子：
5.8
通讯作者：
Min, Weiping
中科院分区：
文献类型：
--
作者：
Zhang, Meng;Gao, Dian;Min, Weiping
抑制受体阻断（IRs）是治疗癌症最有效的免疫治疗方法之一。mirna的功能障碍是导致IRs异常表达的主要原因，并有助于癌细胞的免疫逃逸。在乳腺癌中，mirna如何调节免疫检查点蛋白在很大程度上仍然未知。在本研究中，通过对小鼠乳腺癌同种移植物的miRNA阵列分析，在pd -1过表达的CD8(+) T细胞中观察到miRNA的下调。数据显示，miR-149-3p可以结合编码t细胞抑制剂受体PD-1、TIM-3、BTLA和Foxp1的mrna的3' utr。用miR-149-3p模拟物处理CD8(+) T细胞可减少细胞凋亡，减弱T细胞衰竭mRNA标记物的变化，下调编码PD-1、TIM-3、BTLA和Foxp1的mRNA。另一方面，miR-149-3p模拟处理后，t细胞增殖和表明t细胞活化增加的效应细胞因子（IL-2, tnf - α, ifn - γ）的分泌上调。此外，miR-149-3p模拟物的处理促进了CD8(+) T细胞杀死靶向4T1小鼠乳腺肿瘤细胞的能力。总的来说，这些数据表明miR-149-3p可以逆转CD8(+) t细胞衰竭，并揭示它是乳腺癌中潜在的抗肿瘤免疫治疗剂。
Blockade of inhibitory receptors (IRs) is one of the most effective immunotherapeutic approaches to treat cancer. Dysfunction of miRNAs is a major cause of aberrant expression of IRs and contributes to the immune escape of cancer cells. How miRNAs regulate immune checkpoint proteins in breast cancer remains largely unknown. In this study, downregulation of miRNAs was observed in PD-1-overexpressing CD8(+) T cells using miRNA array analysis of mouse breast cancer homografts. The data reveal that miR-149-3p was predicted to bind the 3'UTRs of mRNAs encoding T-cell inhibitor receptors PD-1, TIM-3, BTLA and Foxp1. Treatment of CD8(+) T cells with an miR-149-3p mimic reduced apoptosis, attenuated changes in mRNA markers of T-cell exhaustion and downregulated mRNAs encoding PD-1, TIM-3, BTLA and Foxp1. On the other hand, T-cell proliferation and secretion of effector cytokines indicative of increased T-cell activation (IL-2, TNF-alpha, IFN-gamma) were upregulated after miR-149-3p mimic treatment. Moreover, the treatment with a miR-149-3p mimic promoted the capacity of CD8(+) T cells to kill targeted 4T1 mouse breast tumour cells. Collectively, these data show that miR-149-3p can reverse CD8(+) T-cell exhaustion and reveal it to be a potential antitumour immunotherapeutic agent in breast cancer.