Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-03348-z
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Funding
- Canceropole Ile-de-France
- Ligue Nationale Contre le Cancer
- Institut National du Cancer (INCa)
- Fondation pour la Recherche Medicale (FRM)
- SiRIC-Curie program [INCa-DGOS-4654]
- Institut National de la Sante et de la Recherche Medicale (Inserm)
- Institut Curie
- PIC TME
- PIC3i CAFi
- Ligue Nationale Contre le Cancer (Labelisation)
- Fondation ARC
- INCa [2011-1-PLBIO-12-IC-1, 2015-1-RT-04-ICR-1]
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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.
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