Prostacyclin Released by Cancer-Associated Fibroblasts Promotes Immunosuppressive and Pro-Metastatic Macrophage Polarization in the Ovarian Cancer Microenvironment

Leah Sommerfeld; Isabel Knuth; Florian Finkernagel; Jelena Pesek; Wolfgang A Nockher; Julia M Jansen; Uwe Wagner; Andrea Nist; Thorsten Stiewe; Sabine Müller-Brüsselbach; Rolf Müller; Silke Reinartz

doi:10.3390/cancers14246154

Prostacyclin Released by Cancer-Associated Fibroblasts Promotes Immunosuppressive and Pro-Metastatic Macrophage Polarization in the Ovarian Cancer Microenvironment

Cancers (Basel). 2022 Dec 13;14(24):6154. doi: 10.3390/cancers14246154.

Authors

Affiliations

¹ Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.
² Bioinformatics Spectrometry Core Facility, Philipps University, 35043 Marburg, Germany.
³ Medical Mass Spectrometry Core Facility, Philipps University, 35043 Marburg, Germany.
⁴ Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, University Hospital (UKGM), 35043 Marburg, Germany.
⁵ Genomics Core Facility, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.

Abstract

Metastasis of high-grade ovarian carcinoma (HGSC) is orchestrated by soluble mediators of the tumor microenvironment. Here, we have used transcriptomic profiling to identify lipid-mediated signaling pathways encompassing 41 ligand-synthesizing enzymes and 23 cognate receptors in tumor, immune and stroma cells from HGSC metastases and ascites. Due to its strong association with a poor clinical outcome, prostacyclin (PGI₂) synthase (PTGIS) is of particular interest in this signaling network. PTGIS is highly expressed by cancer-associated fibroblasts (CAF), concomitant with elevated PGI₂ synthesis, whereas tumor-associated macrophages (TAM) exhibit the highest expression of its surface receptor (PTGIR). PTGIR activation by PGI₂ agonists triggered cAMP accumulation and induced a mixed-polarization macrophage phenotype with altered inflammatory gene expression, including CXCL10 and IL12A repression, as well as reduced phagocytic capability. Co-culture experiments provided further evidence for the interaction of CAF with macrophages via PGI₂, as the effect of PGI₂ agonists on phagocytosis was mitigated by cyclooxygenase inhibitors. Furthermore, conditioned medium from PGI₂-agonist-treated TAM promoted tumor adhesion to mesothelial cells and migration in a PTGIR-dependent manner, and PTGIR activation induced the expression of metastasis-associated and pro-angiogenic genes. Taken together, our study identifies a PGI₂/PTGIR-driven crosstalk between CAF, TAM and tumor cells, promoting immune suppression and a pro-metastatic environment.

Keywords: carcinoma-associated fibroblasts; high-grade serous ovarian carcinoma; pro-metastatic phenotype; prostacyclin; signaling network; tumor-associated macrophages.

Grants and funding

This research was funded by the Deutsche Forschungsgemeinschaft (DFG), grant number MU601/22-1 to RM, and by the German Cancer Aid (Deutsche Krebshilfe), grant number 70113255 to RM and SR.