miRNA-5119 regulates immune checkpoints in dendritic cells to enhance breast cancer immunotherapy
miRNA-5119 regulates immune checkpoints in dendritic cells to enhance breast cancer immunotherapy
复制标题
miRNA-5119 调节树突状细胞中的免疫检查点以增强乳腺癌免疫治疗
DOI：
10.1007/s00262-020-02507-w
复制
发表时间：
2020-02-20
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;Shi, Yanmei;Min, Weiping
基于树突状细胞（DC）的免疫治疗是一种有前途的临床癌症治疗方法。miRNA是一类小的非编码RNA分子，其与RNA结合以介导在多种生物过程中重要的多个事件。miRNA模拟物和miRNA抑制剂可能是增强基于DC的针对癌症的免疫疗法的有效药剂。miRNA阵列分析用于鉴定可能调节DC中PD-L1的代表性miR-5119。我们评估了免疫细胞抑制受体（IR）和miR-5119在免疫活性小鼠乳腺癌荷瘤小鼠DC中的配体水平，并检查了miR-5119的分子靶点。我们报道了miRNA-5119在小鼠乳腺癌荷瘤小鼠脾脏DCs中下调。计算机模拟分析和qPCR数据显示，miRNA-5119靶向编码多种负性免疫调节分子的mRNA，包括IR的配体，如PD-L1和IDO 2。经工程改造表达miR-5119模拟物的DC下调PD-L1并防止乳腺癌同种移植物小鼠中的T细胞耗竭。此外，miR-5119模拟工程化的DC在体外和体内有效地恢复了耗尽的CD 8 +T细胞的功能，导致稳健的抗肿瘤细胞免疫应答，上调细胞因子产生，减少T细胞凋亡和耗尽。用miR-5119模拟工程化DC疫苗治疗4 T1乳腺肿瘤荷瘤小鼠减少了T细胞耗竭并抑制了小鼠乳腺肿瘤同种移植物生长。这项研究提供了证据支持一种新的治疗方法，使用miRNA-5119模拟工程化的DC疫苗来调节抑制性受体并增强小鼠乳腺癌模型中的抗肿瘤免疫应答。基于miRNA/DC的免疫治疗有可能作为基于DC的抗乳腺癌免疫治疗的新策略推进到临床。
Dendritic cell (DC) based immunotherapy is a promising approach to clinical cancer treatment. miRNAs are a class of small non-coding RNA molecules that bind to RNAs to mediate multiple events which are important in diverse biological processes. miRNA mimics and antagomirs may be potent agents to enhance DC-based immunotherapy against cancers. miRNA array analysis was used to identify a representative miR-5119 potentially regulating PD-L1 in DCs. We evaluated levels of ligands of immune cell inhibitory receptors (IRs) and miR-5119 in DCs from immunocompetent mouse breast tumor-bearing mice, and examined the molecular targets of miR-5119. We report that miRNA-5119 was downregulated in spleen DCs from mouse breast cancer-bearing mice. In silico analysis and qPCR data showed that miRNA-5119 targeted mRNAs encoding multiple negative immune regulatory molecules, including ligands of IRs such as PD-L1 and IDO2. DCs engineered to express a miR-5119 mimic downregulated PD-L1 and prevented T cell exhaustion in mice with breast cancer homografts. Moreover, miR-5119 mimic-engineered DCs effectively restored function to exhausted CD8+T cells in vitro and in vivo, resulting in robust anti-tumor cell immune response, upregulated cytokine production, reduced T cell apoptosis, and exhaustion. Treatment of 4T1 breast tumor-bearing mice with miR-5119 mimic-engineered DC vaccine reduced T cell exhaustion and suppressed mouse breast tumor homograft growth. This study provides evidence supporting a novel therapeutic approach using miRNA-5119 mimic-engineered DC vaccines to regulate inhibitory receptors and enhance anti-tumor immune response in a mouse model of breast cancer. miRNA/DC-based immunotherapy has potential for advancement to the clinic as a new strategy for DC-based anti-breast cancer immunotherapy.