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 eighty-five pretreated advanced HGSOC patients, correlating them with baseline CA125, age at diagnosis, BMI and peritoneal carcinomatosis. Univariate and multivariate Cox proportional hazard regression models were built to identify significant prognostic factors for Progression-free Survival (PFS).
A multivariate analysis revealed that plasma BTN3A1≤4.75 ng/mL (HR: 1.94; 95% CI: 1.23 to 3.07; p=0.004), age at diagnosis ≤60 years (HR: 1.65; 95% CI: 1.05 to 2.59; p=0.03) and absence of peritoneal carcinomatosis (HR: 2.65; 95% CI: 1.66 to 4.22; p<0.0001) were independent prognostic factors for a longer PFS (≥30 months) in advanced HGSOC women. However, further analyses showed that each circulating immune checkpoint (PD-1>2.48 ng/mL, PD-L1>0.42 ng/mL, pan-BTN3As>13.06 ng/mL, BTN3A1>4.75 ng/mL, BTN2A1>5.59 ng/mL, BTLA>2.78 ng/mL) individually correlated in a statistically significant way with serum CA125>401 U/mL levels, suggesting shorter PFS (<30 months) and poor prognosis.
Plasma PD-L1, PD-1, BTN3A1, pan-sBTN3As, BTN2A1 or BTLA levels could be helpful biomarkers to increase prognostic value of CA125.
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All authors have declared no conflicts of interest.