Clinical Relevance of Soluble Forms of Immune Checkpoint Molecules sPD-1, sPD-L1, and sCTLA-4 in the Diagnosis and Prognosis of Ovarian Cancer

Abstract

It is crucial to find new diagnostic and prognostic biomarkers. A total of 80 patients were enrolled in the study. The study group consisted of 37 patients with epithelial ovarian cancer, and the control group consisted of 43 patients with benign ovarian cystic lesions. Three proteins involved in the immune response were studied: PD-1, PD-L1, and CTLA-4. The study material was serum and peritoneal fluid. The ROC curve was plotted, and the area under the curve was calculated to characterize the sensitivity and specificity of the studied parameters. Univariate and multivariate analyses were performed simultaneously using the Cox regression model. The cut-off level of CTLA-4 was 0.595 pg/mL, with the sensitivity and specificity of 70.3% and 90.7% (p = 0.000004). Unfavorable prognostic factors determined in serum were: PD-L1 (for PFS: HR 1.18, 95% CI 1.11–1.21, p = 0.016; for OS: HR 1.17, 95% CI 1.14–1.19, p = 0.048) and PD-1 (for PFS: HR 1.01, 95% CI 0.91–1.06, p = 0.035). Unfavorable prognostic factors determined in peritoneal fluid were: PD-L1 (for PFS: HR 1.08, 95% CI 1.01–1.11, p = 0.049; for OS: HR 1.14, 95% CI 1.10–1.17, p = 0.045) and PD-1 (for PFS: HR 1.21, 95% CI 1.19–1.26, p = 0.044). We conclude that CTLA-4 should be considered as a potential biomarker in the diagnosis of ovarian cancer. PD-L1 and PD-1 concentrations are unfavorable prognostic factors for ovarian cancer.

Does Elevated Pre-Treatment Plasma PD-L1 Level Indicate an Increased Tumor Burden and Worse Prognosis in Metastatic Colorectal Cancer?

“…Moreover, CCC patients with higher baseline soluble PD-L1 levels had shorter survival times [ 37 , 38 ]. Similar findings could have been observed for melanoma [ 39 ], gastric [ 40 ], hepatocellular [ 41 , 42 ], urothelial [ 15 ], renal [ 16 , 43 ], ovarian [ 44 ], and lung cancers [ 12 , 14 , 39 , 45 ]: baseline soluble PD-L1 measurements can serve as a good prognostic marker for patient survival and increasing levels are associated with progressive disease. Soluble PD-1 may serve as a good prognostic factor in gastric, lung, and bladder cancers [ 46 ].…”

“…As shown above, soluble PD-L1 is strongly associated with progressive disease and tumor burden, both in CRC [ 13 , 17 , 49 , 50 , 52 ] and in other malignant diseases [ 12 , 14 , 15 , 16 , 37 , 38 , 41 , 42 , 43 , 44 , 45 , 46 ]. Although there are numerous studies investigating membrane-bound PD-1/PD-L1 in various metastatic cancers [ 53 , 54 ], the soluble form has been less examined [ 55 ].…”

Low plasma PD-L1 levels, early tumor onset and absence of peritoneal carcinomatosis improve prognosis of women with advanced high-grade serous ovarian cancer

“…In the last years, circulating PD-1 and PD-L1 levels have been shown to be associated with worse survival in individuals affected by different cancers [ 19 , 20 ]. However, the association between increased levels of soluble PD-1 and PD-L1 and poor clinical outcome has been little investigated so far in OC women [ 31 , 32 ].…”

“…The patients with advanced stage tumors frequently have ascites which could also be a source of several soluble factors such as sPD-L1. A recent study determined the sPD-L1 levels in peritoneal fluid, suggesting its role as unfavorable prognostic factor in OC [ 32 ].…”

Can circulating PD-1, PD-L1, BTN3A1, pan-BTN3As, BTN2A1 and BTLA levels enhance prognostic power of CA125 in patients with advanced high-grade serous ovarian cancer?

“…Recently, several studies highlighted an association between poor prognosis and high plasma PD-1 and PD-L1 concentrations in different tumors ( 21 , 25 , 26 , 28 ), although this correlation has been little studied, to date, in OC patients ( 51 , 52 ).…”