Soluble forms of immune checkpoint receptor PD-1 and its ligand PD-L1 in plasma of patients with ovarian neoplasms

Background: Ovarian cancer is one of the most common oncologic diseases holding the frst place in mortality related to neoplasms of female genitalia. Along with active surgical intervention, contemporary ovarian cancer treatment includes various chemotherapeutic regimens which in many cases are quite effective, but relapse and death rates still remain high. In the recent years, major attention has been paid to the possibility of ovarian cancer immunotherapy associated with the discovery of the so-called “immune checkpoint” signaling, i.e. programmed cell death-1 / programmed death-ligand 1 (PD-1/PD-L) pathway, controlling intensity and duration of autoimmune response at physiologic conditions. Tumor PD-1 and/or PD-L1 expression is being actively studied as a predictor of anti-PD-1/PD-L treatment efficacy; however, this approach has certain limitations and problems that might be probably bypassed by determination of soluble PD-1 (sPD-1) and its ligand (sPD-L1) in serum or plasma.

Aim: Comparative evaluation of sPD-1 and sPD-L1 content in plasma of healthy women and of patients with benign or borderline ovarian tumors and ovarian cancer, as well as the analysis of associations between these markers and main clinical and pathologic characteristics of ovarian cancer.

Materials and methods: Sixty two (62) patients with ovarian neoplasms aged 32 to 77 (median, 56.5) years were enrolled into the study. Fifteen (15) patients had benign tumors, 9 had borderline, and 38, ovarian cancer. The control group included 17 healthy women aged 24 to 67 (median, 49) years. Plasma sPD-L1 and sPD-1 concentrations were measured with standard enzyme immunoassay kits (Afmetrix, eBioscience, USA).

Results: Plasma sPD-L1 and sPD-1 levels in ovarian cancer patients (median, 41.3 and 48.0 pg/ml, respectively) did not differ significantly from those in the control group (49.5 and 43.8 pg/ml). sPD-L1 level in the patients with benign tumors (median, 22.2 pg/ml) was signifcantly lower than in the control (p < 0.01). The lowest sPD-1 level in plasma was found in the patients with borderline ovarian neoplasms, the difference with the ovarian cancer group being statistically signifcant (p < 0.05). No correlations between sPD-L1 and sPD-1 plasma levels were found in any of the study groups. sPD-L1 level signifcantly increased with disease stage (R = 0.44; p < 0.01), the most signifcant increase being observed at the most advanced IIIC stage (p < 0.05 as compared to all other stages). sPD-L1 was also signifcantly higher in the patients with ascites than in those without ascites. Plasma sPD-1 concentration was not associated with the indices of ovarian cancer progression, though its median was 1.3–1.44 times lower in the stage I than in the stage II–III patients, and decreased in those with the tumor size above 10 cm (assessed by ultrasound examination) and in the patients with ascites. No statistically signifcant associations of the markers' levels with tumor histological type and differentiation grade of ovarian cancer were found.

Conclusion: sPD-L1 level in ovarian cancer patients correlates with disease progression and can be considered as a promising marker for monitoring of anti-PD-1/PD-L1 treatment efficacy. Potential clinical implications of sPD-1 require further studies.