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?

Abstract

The most common subtype of ovarian cancer (OC) is the high-grade serous ovarian carcinoma (HGSOC), accounting for 70%-80% of all OC deaths. Although HGSOC is a potentially immunogenic tumor, clinical studies assessing the effectiveness of inhibitors of programmed death protein and its ligand (PD-1/PD-L1) in OC patients so far showed only response rates <15%. However, recent studies revealed an interesting prognostic role of plasma PD-1/PD-L1 and other circulating immunoregulatory molecules, such as the B- and T-lymphocyte attenuator (BTLA), butyrophilin sub-family 3A/CD277 receptors (BTN3A), and butyrophilin sub-family 2 member A1 (BTN2A1), in several solid tumors. Since evidence showed the prognostic relevance of pretreatment serum CA125 levels in OC, the aim of our study was to investigate if soluble forms of inhibitory immune checkpoints can enhance prognostic power of CA125 in advanced HGSOC women. Using specific ELISA tests, we examined the circulating PD-1, PD-L1, pan-BTN3As, BTN3A1, BTN2A1, and BTLA levels in 100 advanced HGSOC patients before treatment, correlating them with baseline serum CA125, age at diagnosis, body mass index (BMI), and peritoneal carcinomatosis. A multivariate analysis revealed that plasma BTN3A1 ≤4.75 ng/ml (HR, 1.94; 95% CI, 1.23-3.07; p=0.004), age at diagnosis ≤60 years (HR, 1.65; 95% CI, 1.05-2.59; p=0.03) and absence of peritoneal carcinomatosis (HR, 2.65; 95% CI, 1.66-4.22; p<0.0001) were independent prognostic factors for a longer progression-free survival (PFS) (≥30 months) in advanced HGSOC women. However, further two-factor multivariate analyses highlighted that baseline serum CA125 levels >401 U/ml and each soluble protein above respective concentration cutoff were covariates associated with shorter PFS (<30 months) and unfavorable clinical outcome, suggesting that contemporary measurement of both biomarkers than CA125 only could strengthen prognostic power of serum CA125 in predicting PFS of advanced HGSOC women. Plasma PD-L1, PD-1, BTN3A1, pan-sBTN3As, BTN2A1, or BTLA levels could be helpful biomarkers to increase prognostic value of CA125.

Keywords: BTLA; HGSOC; PD-1; PD-L1; butyrophilins; circulating immune checkpoints; prognostic factors; serum CA125.

Figure 1

Scatter plots by group discriminating advanced HGSOC patients based on long versus short PFS for each examined factor. The plasma levels of each soluble protein, ages at diagnosis, BMIs, and baseline serous CA125 levels of advanced HGSOC patients were plotted for short (<30 months) versus long PFS (≥30 months). For each considered factor, the red dashed lines represent the optimal thresholds previously calculated by ROC analysis. The concentrations of each biomarker are reported in ng/ml. BMI, body mass index; CA125, cancer antigen 125; PFS, progression-free survival. ****p<0.0001.

Figure 2

Kaplan–Meier analysis of progression-free survival in 100 advanced HGSOC patients with high and low plasma levels of (A) sPD-L1, (B) sPD-1, (C) sBTN3A1, (D) pan-sBTN3As, (E) sBTN2A1, and (F) sBTLA. In addition, Kaplan–Meier analyses showing the correlations between PFS and (G) age at diagnosis, (H) BMI, (I) presence of peritoneal carcinomatosis, and (J) baseline CA125 levels are shown. BMI, body mass index; CA125, cancer antigen 125.

Figure 3

Kaplan–Meier analysis of progression-free survival in 24 advanced HGSOC patients from validation cohort. BMI, body mass index.