Abstract:
: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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Givel AM,Kieffer Y,Scholer-Dahirel A,Sirven P,Cardon M,Pelon F,Magagna I,Gentric G,Costa A,Bonneau C,Mieulet V,Vincent-Salomon A,Mechta-Grigoriou Fdoi
10.1038/s41467-018-03348-zsubject
Has Abstractpub_date
2018-03-13 00:00:00pages
1056issue
1issn
2041-1723pii
10.1038/s41467-018-03348-zjournal_volume
9pub_type
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