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

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 (CXCL12 beta) specifically accumulates in the immunosuppressive CAF-S1 subset through a miR-141/200a dependent-mechanism. Moreover, CXCL12 beta 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 CXCL12 alpha. Thus, our data highlight the differential regulation of the CXCL12 alpha and CXCL12 beta isoforms in HGSOC, and reveal a CXCL12 beta-associated stromal heterogeneity and immunosuppressive environment in mesenchymal HGSOC.