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Ovarian cancer (OvCa) is the tumor with the most unfavourable prognosis among all gynaecological malignancies causing more than 6000 deaths per year in Germany alone. Patients with OvCa show symptoms at very advanced stages of tumor progression when the only available treatments consist on tumor debulking surgery and administration of platinum based chemotherapeutics and anthracyclins. There is an urgent need to develop new therapeutical strategies since the actual 5 year survival rate of OvCa patients does not exceed 20-40%.
Immunotherapy is a promising approach for treatment of ovarian cancer, since it has been observed that immunological parameters can influence the outcome of the patient. The aim of our research is to overcome tumor immune escape by counteracting the immunosuppressive mechanisms developed by the tumor. In particular, this work studies the influence of adenosine generated by the ectonucleotidases CD39 and CD73 in the tumor microenvironment. Cellular expression of CD39 and CD73 contributes to immunosupression as these ectonucleotidases convert immune-stimulatory extracellular ATP into immunosuppressive adenosine. This was primarily described as effector mechanism for regulatory T cells, but may also be important in the tumor microenvironment.
Having found that tumor cells from OvCa-patients express high levels of ATP-depleting ectonucleotidases CD39 and CD73 we set out to investigate a potential immunosuppressive mechanism via adenosine production in the tumor microenvironment. We could measure 30-60 times higher adenosine production by OvCa cell lines and ascites-derived cancer cells as compared to physiological normal conditions. To confirm this putative immune escape mechanism we investigated its effect on several immune cell populations. CFSE-based assays, for example, showed an inhibition of CD4+ T cell proliferation by OvCA cell-derived adenosine. In this context, we have further established an in-vitro assay, where OvCa cells modulate the function of macrophages towards a M2 or tumor associated (TAM) phenotype. Together with the phenotype modulation adenosine exerts chemotactic effects on human monocytes and is thus likely to attract myeloid precursor cells towards the tumor tissue. Moreover, in a microenvironment that is shaped by OvCa cells, human monocytes differentiate into M2 macrophages or TAMs which themselves express significant levels of the adenosine-generating ectonucleotidases CD39 and CD73.
Investigating the regulation of ectonucleotidase expression, we also observed that approaches clinically used to treat OvCa (namely application of doxorubicine or irradiation) influence CD73 and CD39 levels of OvCa and immune cells in vitro. In this study we show how this treatment-induced change in the ATP/adenosine ratio modulates the effector function of different immune cells. Furthermore, we investigate the potential benefit of clinically available small molecule inhibitors for CD39 and CD73 that could relieve immunosuppression in the tumor microenvironment especially in combination with common treatment regimes.