Programmed death ligand-1 over-expression correlates with malignancy and contributes to immune regulation in ovarian cancer

Christian J. Maine, Nor Haslinda Abdul Aziz, Jayanta Chatterjee, Claudia Hayford, Nancy Brewig, Lynsey Whilding, Andrew J. T. George, Sadaf Ghaem-Maghami

The programmed death-1 (PD-1) pathway is important in the maintenance of peripheral tolerance and homeostasis through suppression of T cell receptor signaling. As such, it is employed by many tumors as a means of immune escape. We have investigated the role of this pathway in human ovarian cancer (OC) to assess its potential role as a diagnostic and/or prognostic marker and therapeutic target, following recent clinical trial success of antibody therapy directed at this pathway. We show programmed death ligand-1 (PD-L1) expression on monocytes in the ascites and blood of patients with malignant OC is strikingly higher than those with benign/borderline disease, with no overlap in the values between these groups. We characterize the regulation of this molecule and show a role of IL-10 present in ascitic fluid. Flow cytometric analysis of T cells present in the ascites and blood showed a correlation of PD-1 expression with malignant tumors versus benign/borderline, in a similar manner to PD-L1 expression on monocytes. Finally, we demonstrate functional links between PD-L1 expression on monocytes and OC tumor cells with suppression of T cell responses. Overall, we present data based on samples obtained from women with ovarian cancer, suggesting the PD-1 pathway may be used as a reliable diagnostic marker in OC, as well as a viable target for use with PD-1/PD-L1-directed antibody immunotherapy.