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

Anne-Marie Givel (1) , Yann Kieffer (1) , Alix Scholer-Dahirel (1) , Philemon Sirven (2) , Mélissa Cardon (1) , Floriane Pelon (1) , Ilaria Magagna (1) , Géraldine Gentric (1) , Ana Costa (1) , Claire Bonneau (1) , Virginie Mieulet (1) , Anne Vincent-Salomon (3) , Fatima Mechta-Grigoriou (1)

1 U830 - Unité de génétique et biologie des cancers
2 U932 - Immunité et cancer
3 Service de Pathologie [Institut Curie]

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.

Domaines: Sciences du Vivant [q-bio]; Cancer

Anne-Marie Givel, Yann Kieffer, Alix Scholer-Dahirel, Philemon Sirven, Mélissa Cardon, et al.. miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers. Nature Communications, 2018, 9 (1), pp.1056. ⟨10.1038/s41467-018-03348-z⟩. ⟨inserm-02437797⟩