Medical Laboratory Education Center, Colleges of Basic Medicine and Pharmacology, Jiangxi Academy of Medical Sciences, Nanchang University, Nanchang, China.
Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
Cancer Immunol Immunother. 2020 Jun;69(6):951-967. doi: 10.1007/s00262-020-02507-w. Epub 2020 Feb 20.
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.
树突状细胞 (DC) 为基础的免疫疗法是一种很有前途的临床癌症治疗方法。miRNA 是一类小的非编码 RNA 分子，可与 RNA 结合，介导多种事件，这些事件在多种生物过程中很重要。miRNA 模拟物和反义寡核苷酸可能是增强基于 DC 的癌症免疫疗法的有效药物。通过 miRNA 阵列分析，鉴定了一个代表 miR-5119 的分子，该分子可能在 DC 中调节 PD-L1。我们评估了免疫细胞抑制受体 (IR) 的配体和 DC 中的 miR-5119 在免疫功能正常的荷瘤鼠中的水平，并研究了 miR-5119 的分子靶标。我们报告说，miR-5119 在荷瘤鼠的脾脏 DC 中下调。计算机分析和 qPCR 数据显示，miR-5119 靶向编码多个负性免疫调节分子的 mRNAs，包括 PD-L1 和 IDO2 等 IR 配体。表达 miR-5119 模拟物的 DC 下调 PD-L1，并防止乳腺癌同种异体移植物小鼠的 T 细胞耗竭。此外，miR-5119 模拟物工程化的 DC 在体外和体内有效地恢复了耗竭的 CD8 T 细胞的功能，导致强大的抗肿瘤细胞免疫反应，上调细胞因子产生，减少 T 细胞凋亡和耗竭。用 miR-5119 模拟物工程化的 DC 疫苗治疗 4T1 乳腺癌荷瘤小鼠可减少 T 细胞耗竭并抑制小鼠乳腺癌同种异体移植物的生长。这项研究为使用 miR-5119 模拟物工程化的 DC 疫苗调节抑制性受体并增强乳腺癌小鼠模型中的抗肿瘤免疫反应提供了证据，为 miRNA/DC 为基础的免疫疗法作为基于 DC 的抗乳腺癌免疫疗法的新策略提供了潜在的应用。
