Geburtshilfe Frauenheilkd 2016; 76 - P082
DOI: 10.1055/s-0036-1592708

Mesothelial and tumor cells synergize through the SCF/c-Kit axis for IDO-driven regulatory T cell-mediated immunosuppression in ovarian cancer

K Kübler 1, 2, 3, S Riemann 2, TH Ayub 1, 2, A Abramian 1, C Kaiser 1, MD Keyver-Paik 1, W Barchet 2, W Kuhn 1
  • 1University of Bonn, Department of Obstetrics and Gynecology, Center for Integrated Oncology, Bonn, Deutschland
  • 2University of Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, Center for Integrated Oncology, Bonn, Deutschland
  • 3Broad Institute of MIT and Harvard and Massachusetts General Hospital, Havard Medical School, Boston, Vereinigte Staaten von Amerika

Introduction: High-grade epithelial ovarian cancer (EOC) remains a deadly disease, for which more effective therapeutics are needed. EOC appears particularly amenable to immunotherapeutic strategies and especially the inhibition of immune evasion strategies might confer substantial benefit on outcome. The goal of our analysis was to provide the rationale for future anti-cancer strategies that are able to abrogate immunosuppression.

Material and methods: In 33 women diagnosed with EOC the peritumoral immune cell infiltrate was analyzed by flow cytometry; levels of stem cell factor (SCF) and cytokines/chemokines as well as the activity of indoleamine 2,3-dioxygenase (IDO) by ELISA; c-Kit and IDO expression by rt-PCR. Ascites-derived mesothelial and EOC cell cultures, primary EOC cells and peripheral blood mononuclear cells (PBMC) from healthy donors were used for functional in vitro assays.

Results: Mesothelial-secreted SCF was identified alongside the expression of its receptor c-Kit in a minority of patients. However, in these women the presence of both parts of the signaling pathway correlated with higher IDO activity and an elevated amount of regulatory T cells. These results were confirmed by in vitro assays showing that SCF provokes IDO expression in c-Kit-positive tumors consequently leading to regulatory T cell induction.

Discussion: Our results show that paracrine stimulation via the c-Kit ligand-receptor system is involved in conferring IDO-dependent regulatory T cell-mediated immunosuppression in EOC. This novel interplay between stroma and EOC identifies tolerogenic tumor phenotypes and provides a rationale for the development of individualized immunotherapeutic approaches targeting the SCF/c-Kit axis.