miR200调控的CXCL12β促进卵巢癌成纤维细胞异质性和免疫抑制。

miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers.

作者信息

Givel Anne-Marie, Kieffer Yann, Scholer-Dahirel Alix, Sirven Philemon, Cardon Melissa, Pelon Floriane, Magagna Ilaria, Gentric Géraldine, Costa Ana, Bonneau Claire, Mieulet Virginie, Vincent-Salomon Anne, Mechta-Grigoriou Fatima

机构信息

Institut Curie, Stress and Cancer Laboratory, Equipe labelisée Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005, Paris, France.

U830, Inserm, 75005, Paris, France.

出版信息

Nat Commun. 2018 Mar 13;9(1):1056. doi: 10.1038/s41467-018-03348-z.

High-grade serous ovarian cancers (HGSOC) have been subdivided into molecular subtypes. The mesenchymal HGSOC subgroup, defined by stromal-related gene signatures, is invariably associated with poor patient survival. We demonstrate that stroma exerts a key function in mesenchymal HGSOC. We highlight stromal heterogeneity in HGSOC by identifying four subsets of carcinoma-associated fibroblasts (CAF-S1-4). Mesenchymal HGSOC show high content in CAF-S1 fibroblasts, which exhibit immunosuppressive functions by increasing attraction, survival, and differentiation of CD25FOXP3 T lymphocytes. The beta isoform of the CXCL12 chemokine (CXCL12β) specifically accumulates in the immunosuppressive CAF-S1 subset through a miR-141/200a dependent-mechanism. Moreover, CXCL12β expression in CAF-S1 cells plays a crucial role in CAF-S1 immunosuppressive activity and is a reliable prognosis factor in HGSOC, in contrast to CXCL12α. Thus, our data highlight the differential regulation of the CXCL12α and CXCL12β isoforms in HGSOC, and reveal a CXCL12β-associated stromal heterogeneity and immunosuppressive environment in mesenchymal HGSOC.

高级别浆液性卵巢癌（HGSOC）已被细分为分子亚型。由基质相关基因特征定义的间充质HGSOC亚组总是与患者的不良生存相关。我们证明基质在间充质HGSOC中发挥关键作用。我们通过鉴定癌相关成纤维细胞的四个亚群（CAF-S1-4）来突出HGSOC中的基质异质性。间充质HGSOC在CAF-S1成纤维细胞中含量较高，这些细胞通过增加CD25FOXP3 T淋巴细胞的吸引、存活和分化而表现出免疫抑制功能。趋化因子CXCL12的β异构体（CXCL12β）通过miR-141/200a依赖性机制特异性地积聚在免疫抑制性CAF-S1亚群中。此外，与CXCL12α相反，CAF-S1细胞中CXCL12β的表达在CAF-S1免疫抑制活性中起关键作用，并且是HGSOC中可靠的预后因素。因此，我们的数据突出了HGSOC中CXCL12α和CXCL12β异构体的差异调节，并揭示了间充质HGSOC中与CXCL12β相关的基质异质性和免疫抑制环境。