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

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

Edité par CCSD ; Nature Publishing Group -

International audience. 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 CD25 + FOXP3 + 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.

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