Cancer-Associated Fibroblasts-Derived Exosomes Suppress Immune Cell Function in Breast Cancer via the miR-92/PD-L1 Pathway.
Cancer-Associated Fibroblasts-Derived Exosomes Suppress Immune Cell Function in Breast Cancer via the miR-92/PD-L1 Pathway.
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DOI：
10.3389/fimmu.2020.02026
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发表时间：
2020
影响因子：
7.3
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Dou D;Ren X;Han M;Xu X;Ge X;Gu Y;Wang X
癌症相关成纤维细胞（CAF）是肿瘤微环境中的重要组成部分，并已报道通过多种机制促进肿瘤进展;然而，CAF免疫抑制作用的详细机制尚未明确定义。在本研究中，培养人乳腺癌来源的CAF，并分离培养基中的CAF来源的外泌体。使用miRNA谱分析，我们鉴定了在CAF外泌体中分离的显著更高水平的microRNA-92。在用CAF衍生的外泌体处理后，乳腺癌细胞表达更高的程序性细胞死亡受体配体1（PD-L1），伴随着miR-92表达的增加。由CAF衍生的外泌体诱导的PD-L1表达增加显著促进T细胞的凋亡和受损的增殖。对这种作用的机制进行了研究，发现转染miR-92后乳腺癌细胞的增殖和迁移增加，LATS 2被认为是miR-92的靶基因，并通过荧光素酶检测进一步证实。免疫沉淀结果显示LATS 2可以与YAP 1相互作用，染色质免疫沉淀结果证实，核转位后的YAP 1可以与PD-L1的增强子区域结合，从而促进转录活性。此外，动物研究证实，CAF在体内显著促进肿瘤进展并损害肿瘤浸润的免疫细胞的功能。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。
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 in vivo. Our data revealed a novel mechanism that can induce immune suppression in the tumor microenvironment.
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DOI：
10.1146/annurev.pathol.4.110807.092222
发表时间：
2009
期刊：
Annual review of pathology
影响因子：
--
作者：
Lee YS;Dutta A
通讯作者：
Dutta A
影响因子：
8
作者：
Richards KE;Zeleniak AE;Fishel ML;Wu J;Littlepage LE;Hill R
通讯作者：
Hill R
影响因子：
--
作者：
Sabatier R;Finetti P;Mamessier E;Adelaide J;Chaffanet M;Ali HR;Viens P;Caldas C;Birnbaum D;Bertucci F
通讯作者：
Bertucci F
影响因子：
16
作者：
Lobb RJ;Becker M;Wen SW;Wong CS;Wiegmans AP;Leimgruber A;Möller A
通讯作者：
Möller A
影响因子：
--
作者：
Acunzo, Mario;Romano, Giulia;Croce, Carlo M
通讯作者：
Croce, Carlo M