Open AccessmiR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers
Author(s) -
Anne-Marie Givel,
Yann Kieffer,
Alix Scholer-Dahirel,
Philémon Sirven,
Mélissa Cardon,
Floriane Pelon,
Ilaria Magagna,
Géraldine Gentric,
Ana Costa,
Claire Bonneau,
Virginie Mieulet,
Anne VincentSalomon,
Fatima MechtaGrigoriou
Publication year - 2018
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/s41467-018-03348-z
Subject(s) - mesenchymal stem cell , stromal cell , cancer research , ovarian carcinoma , immunosuppression , foxp3 , biology , stroma , chemokine , cancer , ovarian cancer , immunology , microbiology and biotechnology , immunohistochemistry , immune system , genetics
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.