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.
Highlights
High-grade serous ovarian cancers (HGSOC) have been subdivided into molecular subtypes
Among viable cells detected by FACS using fresh human HGSOC, we identified epithelial, immune, and endothelial cells using EPCAM, CD45, and CD31 markers, respectively (Fig. 1d, left)
CXCL12 is required for Carcinoma-associated fibroblasts (CAF)-S1-mediated Tlymphocyte attraction in HGSOC, consistent with previous observations in pancreatic cancers[37,38]
Summary
High-grade serous ovarian cancers (HGSOC) have been subdivided into molecular subtypes. Mesenchymal HGSOC show high content in CAF-S1 fibroblasts, which exhibit immunosuppressive functions by increasing attraction, survival, and differentiation of CD25+FOXP3+ T lymphocytes. While the role of the chemokine (CX-C motif) ligand 12 (CXCL12) on HGSOC patient survival remains controversial and the impact of the different CXCL12 isoforms is still largely unknown[22,23,24], we highlight here that CXCL12α and CXCL12β isoforms accumulate differentially in the two subsets of activated fibroblasts identified (namely CAF-S1 and CAF-S4). Our work highlights for the first-time stromal heterogeneity in HGSOC and uncover the specific regulation and function of the CXCL12β isoform in defining stromal and immune features in mesenchymal HGSOC, one of the most deleterious subtypes of ovarian cancers
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