Dataset Information

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.

SUBMITTER: Bian B

PROVIDER: S-EPMC6422385 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

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

Bian Benjamin B Fanale Daniele D Dusetti Nelson N Roque Julie J Pastor Sonia S Chretien Anne-Sophie AS Incorvaia Lorena L Russo Antonio A Olive Daniel D Iovanna Juan J

Oncoimmunology 20190203 4

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 th ...[more]

PMID: 30906655

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Project description: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.

Project description:BackgroundErythropoietin (Epo) administration has been reported to have tumor-promoting effects in anemic cancer patients. We investigated the prognostic impact of endogenous Epo in patients with pancreatic ductal adenocarcinoma (PDAC).MethodologyThe clinico-pathological relevance of hemoglobin (Hb, n = 150), serum Epo (sEpo, n = 87) and tissue expression of Epo/Epo receptor (EpoR, n = 104) was analyzed in patients with PDAC. Epo/EpoR expression, signaling, growth, invasion and chemoresistance were studied in Epo-exposed PDAC cell lines.ResultsCompared to donors, median preoperative Hb levels were reduced by 15% in both chronic pancreatitis (CP, p<0.05) and PDAC (p<0.001), reaching anemic grade in one third of patients. While inversely correlating to Hb (r = -0.46), 95% of sEPO values lay within the normal range. The individual levels of compensation were adequate in CP (observed to predicted ratio, O/P = 0.99) but not in PDAC (O/P = 0.85). Strikingly, lower sEPO values yielding inadequate Epo responses were prominent in non-metastatic M0-patients, whereas these parameters were restored in metastatic M1-group (8 vs. 13 mU/mL; O/P = 0.82 vs. 0.96; p<0.01)--although Hb levels and the prevalence of anemia were comparable. Higher sEpo values (upper quartile ≥ 16 mU/ml) were not significantly different in M0 (20%) and M1 (30%) groups, but were an independent prognostic factor for shorter survival (HR 2.20, 10 vs. 17 months, p<0.05). The pattern of Epo expression in pancreas and liver suggested ectopic release of Epo by capillaries/vasa vasorum and hepatocytes, regulated by but not emanating from tumor cells. Epo could initiate PI3K/Akt signaling via EpoR in PDAC cells but failed to alter their functions, probably due to co-expression of the soluble EpoR isoform, known to antagonize Epo.Conclusion/significanceHigher sEPO levels counteract anemia but worsen outcome in PDAC patients. Further trials are required to clarify how overcoming a sEPO threshold ≥16 mU/ml by endogenous or exogenous means may predispose to or promote metastatic progression.

Project description:Exosomal PD-L1 (exoPD-L1) is reported to be associated with immunosuppression in various cancers. However, its clinical value in extranodal NK/T cell lymphoma (ENKTL) has not been defined yet. We retrospectively evaluated the prognostic value of pretreatment circulating soluble PD-L1 (sPD-L1) and exosomal PD-L1 (exoPD-L1) in ENKTL patients treated with VIPD-containing chemotherapy. A total of 107 ENKTL patients, including 101 early stage and 6 advanced stage patients were enrolled in our study. ExoPD-L1 and sPD-L1 in the blood were measured by single molecule array (Simoa) and enzyme-linked immunosorbent assay (ELISA), respectively. Compared with the healthy individuals (n=16), the patients with ENKTL (n=107) exhibited significantly elevated exoPD-L1 and sPD-L1 levels in the blood. High pretreatment plasma exoPD-L1 concentration was associated with higher SUVmax level and recurrence rate. Similarly, high sPD-L1 group was also associated with some adverse clinical parameters, including advanced stage, elevated LDH levels, B symptoms, high IPI score and PINK score. The 5-year progression-free survival (PFS) rate and overall survival (OS) rates were 65.2% and 85.7% for the whole cohort, respectively. Patients with a low pretreatment exoPD-L1 level (simoa signal < 1.2) had 5-year OS and PFS rates of 88.1% and 86.1%, respectively, compared with 56.0%. (P=0.012) and 35.7% (P=0.007) in patients with high exoPD-L1 level (simoa signal > 1.2). The 5-year OS and PFS rates for patients with low sPD-L1 group (< 219 pg/mL) was significantly higher than high sPD-L1 group (≥ 219 pg/mL) (OS, 91.3% vs. 55.5%, P < 0.001; PFS, 68.9% vs. 34.6%, P=0.003). However, no correlation was found between circulating exoPD-L1 and sPD-L1 levels. This is the first study to measure plasma exoPD-L1 level on the Quanterix Simoa platform. Our results proved that circulating exoPD-L1 and sPD-L1 levels were significantly elevated in ENKTL and might be potential biomarkers for predicting the survival outcomes of ENKTL patients.

Dataset Information

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

Publications

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

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