Prognostic significance of circulating PD-1, PD-L1, pan-BTN3As, BTN3A1 and BTLA in patients with pancreatic adenocarcinoma

Abstract

PDAC is one of the most heterogeneous cancers with low chemotherapeutic sensitivity due to a dense stroma, a weak vasculature and significant biological aggressivity. In cancer, suppressive immune checkpoints are often hyper-activated to ensure an effective evasion of tumor cells from immune surveillance. These immune checkpoints include in part, the B7/butyrophilin-like receptors such as butyrophilin sub-family 3A/CD277 receptors (BTN3A), the B and T lymphocyte attenuator (BTLA) belonging to the B7-like receptors and the programmed death protein (PD-1) with its ligand PD-L1. We evaluated the plasma level of these markers in 32 PDAC patients (learning cohort) by ad hoc developed ELISA's and showed that there are highly correlated. We used ROC curves and univariate analysis to characterize their prognostic relevance in these patients and showed that their plasma level can serve as survival predictor. Plasma level thresholds that correlate with less than six months survival were established for sPD-1 (>8.6 ng/ml), sPD-L1 (>0.36 ng/ml), sBTLA (>1.91 ng/ml), sBTN3A1 (>6.98 ng/ml) and pan-sBTN3A (>6.92 ng/ml). These thresholds were applied in independent validation cohort composed by 27 new samples and could efficiently discriminate short versus long PDAC survivors. Our study reveals that monitoring the concentration of soluble forms of inhibitory immune checkpoints in plasma can help predict survival in PDAC patients and therefore improve their treatments.

Baseline plasma levels of soluble PD-1, PD-L1, and BTN3A1 predict response to nivolumab treatment in patients with metastatic renal cell carcinoma: a step toward a biomarker for therapeutic decisions

“…The BTN3A isoforms is overexpressed in several tumors and involved in the antitumor function of Vγ9Vδ2 cytolytic T-cells. 27 The findings in this study confirm its involvement in the anti-tumor immune response and a potential role as target of novel antitumoral treatments.…”

“…24 Among several immune checkpoints, a family of transmembrane glycoproteins belonging to the immunoglobulin (Ig) superfamily, called butyrophilins (BTNs), has been recently shown to have an interesting immunomodulatory role. [25][26][27] Based on these evidence, we investigated the potential role of sPD-1, sPD-L1, and sBTNs (pan-sBTN3A, sBTN3A1, and sBTN2A1) levels as predictive biomarkers of response to nivolumab treatment in mccRCC patients (Figure 1).…”

Clinical significance of circulating soluble immune checkpoint proteins in sorafenib-treated patients with advanced hepatocellular carcinoma

“…1a). A previous study on pancreatic adenocarcinoma also indicated a negative correlation between plasma levels of sBTLA and OS 28 . BTLA is expressed www.nature.com/scientificreports www.nature.com/scientificreports/ in immune cells, including T cells 29 , and inhibits T cell activation in the late phase of immune responses 30 .…”

Investigation of BTLA tagging variants with risk of esophagogastric junction adenocarcinoma

“…A previous study indicated that the up-regulation of BTLA gene expression and soluble BTLA (sBTLA) was validated in thymoma-associated myasthenia gravis [11]. A prognostic investigation showed that the levels of immune checkpoints sBTLA could be considered as a biomarker for unresectable pancreatic adenocarcinoma cases with a poor survival [12]. A functional study identified that IFN-γ level in circulating T-lymphocytes could be promoted by inhibiting BTLA/HVEM pathway [13].…”