AUTHOR=Buderath Paul , Schwich Esther , Jensen Christina , Horn Peter A. , Kimmig Rainer , Kasimir-Bauer Sabine , Rebmann Vera 

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

JOURNAL=Frontiers in Oncology

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.01015

DOI=10.3389/fonc.2019.01015

ISSN=2234-943X

ABSTRACT=<p><bold>Introduction:</bold> 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.</p><p><bold>Methods:</bold> sPD-L1 and sPD-L2 were determined by ELISA in patients (<italic>N</italic> = 83) and healthy females (<italic>N</italic> = 29). Gene expression analysis of EpCAM, MUC-1, CA-125, and ERCC1 was performed by RT-PCR after CTCs enrichment.</p><p><bold>Results:</bold> sPD-L1 was significantly (<italic>p</italic> = 0.0001) increased and sPD-L2 decreased (<italic>p</italic> = 0.003) in EOC patients compared to controls. While enhanced sPD-L1 was associated with residual tumor burden (<italic>p</italic> = 0.022), reduced sPD-L2 levels were related to platinum-resistance (<italic>p</italic> &lt; 0.01) and the presence of ERCC1+ CTCs (<italic>p</italic> &lt; 0.0001). High sPD-L1 levels were associated with a reduced 5 year overall survival (OS, <italic>p</italic> = 0.003) and progression-free survival (PFS, <italic>p</italic> = 0.019). Strikingly, sPD-L1 levels &gt;6.4 pg/ml were indicative of a reduced OS (<italic>p</italic> = 0.035) and PFS (<italic>p</italic> = 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.</p><p><bold>Conclusions:</bold> 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.</p>