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Response to platinum-based therapy is a major prognostic factor in epithelial ovarian cancer (EOC) and reliable prognostic biomarkers are urgently needed to identify patients at high risk. Since ligands of the Programmed Death Receptor-1 (PD-L1 and PD-L2) play a crucial role within the tumor microenvironment for tumorigenesis, we investigated levels of sPD-L1 and sPD-L2 in liquid biopsies of serum samples, and correlated the results with the clinical status, presence of circulating tumor cells (CTCs) and disease outcome in primary EOC patients.   Methods:  sPD-L1 and sPD-L2 were determined by ELISA in patients ( N  = 83) and healthy females ( N  = 29). Gene expression analysis of EpCAM, MUC-1, CA-125, and ERCC1 was performed by RT-PCR after CTCs enrichment.   Results:  sPD-L1 was significantly ( p  = 0.0001) increased and sPD-L2 decreased ( p  = 0.003) in EOC patients compared to controls. While enhanced sPD-L1 was associated with residual tumor burden ( p  = 0.022), reduced sPD-L2 levels were related to platinum-resistance ( p  < 0.01) and the presence of ERCC1+ CTCs ( p  < 0.0001). High sPD-L1 levels were associated with a reduced 5 year overall survival (OS,  p  = 0.003) and progression-free survival (PFS,  p  = 0.019). Strikingly, sPD-L1 levels >6.4 pg/ml were indicative of a reduced OS ( p  = 0.035) and PFS ( p  = 0.083) in platinum-sensitive patients, while OS and PFS in platinum-resistant patients did not differ when patients were stratified to this cut-off.   Conclusions:  Our study highlights sPD-L1 and sPD-L2 as complementary biomarkers reflecting clinical status, treatment response and disease outcome of EOC patients. Especially, sPD-L1 may facilitate the identification of high-risk patients with unfavorable disease outcomes despite platinum-sensitivity arguing for additional therapeutic approaches. As sPD-L1 and sPD-L2 are easily accessible via liquid biopsy, the inclusion of sPD-L1 and sPD-L2 in addition to CTC investigation as markers for risk assessment during patient therapy planning and follow-up appears to be a valuable approach.

Soluble Programmed Death Receptor Ligands sPD-L1 and sPD-L2 as Liquid Biopsy Markers for Prognosis and Platinum Response in Epithelial Ovarian Cancer