Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Information, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Front Immunol. 2020 Oct 9;11:2026. doi: 10.3389/fimmu.2020.02026. eCollection 2020.
Cancer-associated fibroblasts (CAFs) are an essential component in the tumor microenvironment and have been reported to contribute to tumor progression through many mechanisms; however, the detailed mechanism underlying the immune-suppression effect of CAFs is not clearly defined. In this study, human breast cancer-derived CAFs were cultured, and CAF-derived exosomes in a culture medium were isolated. Using a miRNA profiles assay, we identify a significantly higher level of microRNA-92 isolated in CAFs exosomes. After treatment by CAF-derived exosomes, breast cancer cells express higher programmed cell death receptor ligand 1 (PD-L1), accompanied with increased miR-92 expression. Increased PD-L1 expression, which was induced by CAF-derived exosomes, significantly promotes apoptosis and impaired proliferation of T cells. The underlying mechanism of this effect was studied, proliferation and migration of breast cancer cells were increased after the transfection of miR-92, LATS2 was recognized as a target gene of miR-92, and further confirmed by a luciferase assay. Immunoprecipitation showed that LATS2 can interact with YAP1, chromatin immunoprecipitation confirmed that after nuclear translocation YAP1 could bind to the enhancer region of PD-L1 to promotes transcription activity. Furthermore, the animal study confirmed that CAFs significantly promoted tumor progression and impaired the function of tumor-infiltrated immune cells . Our data revealed a novel mechanism that can induce immune suppression in the tumor microenvironment.
癌症相关成纤维细胞（CAFs）是肿瘤微环境的重要组成部分，已被报道通过多种机制促进肿瘤进展；然而，CAFs 免疫抑制作用的详细机制尚不清楚。在这项研究中，培养了人乳腺癌来源的 CAFs，并分离了培养基中的 CAF 衍生的外泌体。通过 miRNA 谱分析，我们鉴定出 CAFs 外泌体中 microRNA-92 的水平显著升高。用 CAF 衍生的外泌体处理后，乳腺癌细胞表达更高水平的程序性死亡受体配体 1（PD-L1），同时伴有 miR-92 表达增加。CAF 衍生的外泌体诱导的 PD-L1 表达增加显著促进 T 细胞凋亡和增殖受损。研究了这种作用的潜在机制，miR-92 的转染增加了乳腺癌细胞的增殖和迁移，LATS2 被认为是 miR-92 的靶基因，并通过荧光素酶测定进一步证实。免疫沉淀显示 LATS2 可以与 YAP1 相互作用，染色质免疫沉淀证实，核转位后 YAP1 可以与 PD-L1 的增强子区域结合，促进转录活性。此外，动物研究证实 CAFs 显著促进肿瘤进展并损害肿瘤浸润免疫细胞的功能。我们的数据揭示了一种新的机制，可以在肿瘤微环境中诱导免疫抑制。
