miR-200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers

High-grade serous epithelial ovarian cancer (HGSOC) has been recently subdivided into molecular subgroups, including the mesenchymal HGSOC associated with partial tumor-debulking surgery and poor patient survival. Consistent with stromal-related genes signatures defining mesenchymal HGSOC, we show here that stroma plays a key function in this HGSOC molecular subtype. We first highlight stromal heterogeneity in HGSOC by identifying 4 subsets of Carcinoma-Associated Fibroblast (CAF-S1-4). Mesenchymal HGSOC significantly accumulate the activated CAF-S1 subset, which exhibits immunosuppressive functions by promoting attraction, survival and activation of regulatory T-lymphocytes. The CXCL12β chemokine reliably characterizes mesenchymal HGSOC and specifically accumulates in the CAF-S1 subset through a regulation mediated by the miR-141/200a. CXCL12β promotes attraction of T-lymphocytes and is thus a key actor in CAF-S1-mediated immunosuppressive functions. In conclusion, we highlight here for the first time stromal heterogeneity and immunosuppression in mesenchymal HGSOC that could participate in the poor patient prognosis.EGA study EGAS00001002184

高级别浆液性上皮性卵巢癌（High-grade serous epithelial ovarian cancer, HGSOC）近期被划分为多个分子亚型，其中间质型HGSOC与不完全肿瘤细胞减灭术及患者预后不良密切相关。与定义间质型HGSOC的间质相关基因特征相符，本研究证实间质微环境在该分子亚型HGSOC中发挥关键调控作用。我们首先通过鉴定4个癌相关成纤维细胞（Carcinoma-Associated Fibroblast, CAF-S1至CAF-S4）亚型，阐明了HGSOC的间质异质性。间质型HGSOC显著富集激活型CAF-S1亚型，该亚型可通过促进调节性T淋巴细胞的趋化、存活与活化发挥免疫抑制功能。趋化因子CXCL12β可特异性表征间质型HGSOC，并通过miR-141/200a介导的调控通路特异性富集于CAF-S1亚型中。CXCL12β可促进T淋巴细胞趋化，是CAF-S1介导的免疫抑制功能中的核心效应因子。综上，本研究首次揭示了间质型HGSOC中的间质异质性与免疫抑制机制，该机制或参与介导患者的不良预后。本研究相关数据来自EGA研究EGAS00001002184。