CD117+/c-Kit+ cancer stem cells exhibit immune-modulatory effects in high-grade serous ovarian cancer

Aim High-grade serous ovarian cancer (HGSOC) remains a fatal disease with a majority of patients experiencing relapse and resistance to chemotherapy. One potential reason for this clinical course is tumor immune evasion, such as induced by the enzyme Idoleamine 2,3-Dioxygenase 1 (IDO1). Here, we investigated the influence of putative CD117+/c-Kit+ cancer stem cells (CSCs) on the IDO-pathway and the subsequent immune-modulation.

Materials Ascites of 31 women with HGSOC, ascites-derived primary mesothelial and tumor cell cultures as well as established ovarian cancer cell lines were used to analyze tolerogenic mechanisms. Furthermore, matched formalin-fixed paraffin-embedded solid tumor tissue samples of these patients were used for immunohistochemical analysis.

Methods The peritumoral immune cell infiltrate was evaluated by flow cytometry and immunohistochemistry; levels of stem cell factor (SCF) and other cytokines/chemokines were quantified by ELISA; c-Kit expression and IDO1 activity were determined by RT-qPCR and ELISA. SKOV3 and CAOV3 cell-lines were used to establish a model system for the evaluation of CD117/c-Kit activation.

Results We found that CD117+/c-Kit+ tumor cells are rare, suggesting a stem cell state. However, the stimulation of CD117+/c-Kit+ HGSOC cells with SCF increased IDO1 expression and further caused an induction of immunosuppressive regulatory T cells. This effect could be reversed when blocking CD117/c-Kit with the drug Imatinib.

Summary Our data suggest that CD117+/c-Kit+ putative CSCs are able to exert immune modulatory effects in the tumor microenvironment of HGSOC by influencing IDO1 via an increase in regulatory T-cells.

Publication History

Article published online:
07 October 2020