Elevated sPD-L1 Research Articles

Correlation of Soluble Programmed Death Ligand-1 (sPD-L1) with Alpha-Fetoprotein Levels as a Predictor of Prognosis in Hepatocellular Carcinoma Patients

Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and one of the leading causes of cancer death worldwide. Chronic hepatitis B virus infection is the most common etiology of HCC. Programmed death ligand-1 (PD-L1) is a protein that is overexpressed on the surface of tumor cells, which can be detected in serum (sPD-L1). Elevated sPD-L1 concentrations in the plasma of cancer patients are associated with poor prognosis in HCC patients, as indicated by increased AFP levels. There have been no previous studies examining the correlation of sPD-L1 levels with AFP in HCC patients. The aim of the study was to determine the correlation of sPD-L1 and AFP as predictors of prognosis in HCC patients.
 Methods: The research is an observational study with a cross-sectional design to see the correlation of sPD-L 1 with serum alpha-fetoprotein levels in HCC patients at Dr. Mohammad Hoesin General Hospital Palembang starts from April to July 2023. Measurement of sPD-L1 levels and serum AFP levels is carried out using ELISA examination.
 Results: Of the 28 subjects studied, HCC patients were more commonly found in men (89.29%) aged 18-60 years (75%). sPD-L1 and AFP values were found to be increased in the advanced stages of HCC. The sPD-L1 value is directly proportional to the serum AFP value.
 Conclusion: There is a strong positive correlation between sPD-L1 levels and serum AFP levels caused by hepatitis B in HCC patients, so the higher the sPD-L1, the higher the serum AFP levels.

Prognostic significance of soluble PD-L1 in prostate cancer.

The aim of this study was to assess the role of sPD-L1 and sPD-1 as potential biomarkers in prostate cancer (PCa). The association of the values of these soluble proteins were correlated to the clinical data: stage of disease, Gleason score, biochemical recurrence etc. For a comprehensive study, the relationship between sPD-L1 and sPD-1 and circulating immune cells was further investigated. A total of 88 patients with pT2 and pT3 PCa diagnosis and 41 heathy men were enrolled. Soluble sPD-L1 and sPD-1 levels were measured in plasma by ELISA method. Immunophenotyping was performed by flow cytometry analysis. Our study's findings demonstrate that PCa patients had higher levels of circulating sPD-L1 and sPD-1 comparing to healthy controls (p < 0.001). We found a statistically significant (p < 0.05) relationship between improved progression free survival and lower initial sPD-L1 values. Furthermore, patients with a lower sPD-1/sPD-L1 ratio were associated with a higher probability of disease progression (p < 0.05). Additionally, a significant (p < 0.05) association was discovered between higher Gleason scores and elevated preoperative sPD-L1 levels and between sPD-1 and advanced stage of disease (p < 0.05). A strong correlation (p < 0.05), between immunosuppressive CD4+CD25+FoxP3+ regulatory T cells and baseline sPD-L1 was observed in patients with unfavorable postoperative course of the disease, supporting the idea that these elements influence each other in cancer progression. In addition to the postoperative drop in circulating PD-L1, the inverse relationship (p < 0.05), between the percentage of M-MDSC and sPD-L1 in patients with BCR suggests that M-MDSC is not a source of sPD-L1 in PCa patients. Our findings suggest the potential of sPD-L1 as a promising prognostic marker in prostate cancer.

Thymoquinone, a Novel Multi-Strike Inhibitor of Pro-Tumorigenic Breast Cancer (BC) Markers: CALR, NLRP3 Pathway and sPD-L1 in PBMCs of HR+ and TNBC Patients.

Breast cancer (BC) is not only a mass of malignant cells but also a systemic inflammatory disease. BC pro-tumorigenic inflammation has been shown to promote immune evasion and provoke BC progression. The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is activated when pattern recognition receptors (PRRs) sense danger signals such as calreticulin (CALR) from damaged/dying cells, leading to the secretion of interleukin-1β (IL-1β). CALR is a novel BC biological marker, and its high levels are associated with advanced tumors. NLRP3 expression is strongly correlated with an elevated proliferative index Ki67, BC progression, metastasis, and recurrence in patients with hormone receptor-positive (HR+) and triple-negative BC (TNBC). Tumor-associated macrophages (TAMs) secrete high levels of IL-1β promoting endocrine resistance in HR+ BC. Recently, an immunosuppressive soluble form of programmed death ligand 1 (sPD-L1) has been identified as a novel prognostic biomarker in triple-negative breast cancer (TNBC) patients. Interestingly, IL-1β induces sPD-L1 release. BC Patients with elevated IL-1β and sPD-L1 levels show significantly short progression-free survival. For the first time, this study aims to investigate the inhibitory impact of thymoquinone (TQ) on CALR, the NLRP3 pathway and sPD-L1 in HR+ and TNBC. Blood samples were collected from 45 patients with BC. The effect of differing TQ concentrations for different durations on the expression of CALR, NLRP3 complex components and IL-1β as well as the protein levels of sPD-L1 and IL-1β were investigated in the peripheral blood mononuclear cells (PBMCs) and TAMs of TNBC and HR+ BC patients, respectively. The findings showed that TQ significantly downregulated the expression of CALR, NLRP3 components and IL-1β together with the protein levels of secreted IL-1β and sPD-L1. The current findings demonstrated novel immunomodulatory effects of TQ, highlighting its potential role not only as an excellent adjuvant but also as a possible immunotherapeutic agent in HR+ and TNBC patients.

Soluble PD-L1 as a diagnostic and prognostic biomarker in resectable gastric cancer patients.

In this study, we compared programmed death-ligand 1 (PD-L1) expression in primary tissue samples and its soluble form (sPD-L1) concentration in matched preoperative plasma samples from gastric cancer patients to understand the relationship between tissue and plasma PD-L1 expression and to determine its diagnostic and prognostic value. PD-L1 expression in tissue was assessed by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), and sPD-L1 concentration in plasma was quantified by ELISA. The levels of the CD274 gene, which encodes for PD-L1 protein, were examined as part of bulk tissue RNA-sequencing analyses. Additionally, we evaluated the association between sPD-L1 levels and various laboratory parameters, disease characteristics, and patient outcomes. GC patients had significantly higher levels of sPD-L1 in their plasma (71.69pg/mL) compared to healthy controls (35.34pg/mL) (p < 0.0001). Moreover, sPD-L1 levels were significantly correlated with tissue PD-L1 protein, CD274 mRNA expression, larger tumor size, advanced tumor stage, and lymph node metastasis. Elevated sPD-L1 levels (> 103.5ng/mL) were associated with poor overall survival (HR = 2.16, 95%CI 1.15-4.08, p = 0.017). Furthermore, intratumoral neutrophil and dendritic cell levels were directly correlated with plasma sPD-L1 concentration in the GC patients. sPD-L1 was readily measurable in GC patients, and its level was associated with GC tissue PD-L1 expression, greater inflammatory cell infiltration, disease progression, and survival. Thus, sPD-L1 may be a useful minimally invasive diagnostic and prognostic biomarker in GC patients.

Analysis of soluble programmed death-1 ligand-1 of lung cancer patients with different characteristics.

To analyze the association of soluble programmed death-1 ligand-1 (sPD-L1) levels with clinicopathological characteristics, therapy efficacy, and survival outcomes in lung cancer patients. The study included two hundred treatment-naive patients with small cell lung cancer (SCLC) (n=12), and non-small cell lung cancer (NSCLC) (n=188). Plasma samples from 96 healthy individuals and 13 patients with benign tumors served as controls. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate sPD-L1 expression. Blood samples of 67 NSCLC patients before and after therapy were collected. sPD-L1 expression was significantly higher in lung cancer patients compared to the control groups (p=0.002). Moreover, patients with lower performance status had significantly higher sPD-L1 levels (p=0.005). NSCLC patients at later stages of the disease had greater sPD-L1 levels than those at the early stages (p<0.001). The presence of epidermal growth factor receptor (EGFR) mutation was not significantly different with higher sPD-L1 expression (p=0.334). Although sPD-L1 levels and progression-free survival (PFS) were linked with excellent response to therapy and advancing disease (p=0.307), no correlation was seen between sPD-L1 decrease and progression free survival (PFS). Elevated sPD-L1 expression in NSCLC patients was associated with more advanced disease and worse overall health of the patients, suggesting a possible association with a negative clinical response and prognosis. sPD-L1 expression may be influenced by the mutation in EGFR.

Immune status in chronic critical illness: a systematic review

INTRODUCTION: Currently, there is an increase in the number of patients who are classified as chronically critically ill patients. OBJECTIVE: The review is aimed at studying the indicators of the immune status of chronically critically ill patients. MATERIALS AND METHODS: PubMed and Google Scholar were used to identify relevant articles. The following 3 searches were performed: “chronically critically ill patients AND immune”, “chronic critical illness AND immune”, “persistent inflammation, immunosuppression, and catabolism syndrome AND immune”. The literature review was limited from 2012 to August 2022. The inclusion criteria were as follows: (1) patients with chronic critical illness (CCI) or persistent inflammation, immunosuppression and catabolism syndrome (PICS); (2) comparison groups are at least one of the specified — patients undergoing rapid recovery, healthy volunteers; (3) parameters of the immune status, inflammation and catabolism are the study endpoints; (4) original articles. To assess the validity of the results, a risk of bias assessment was performed for each study included in the analysis. The risk of bias in non-randomised studies of exposures (ROBINS-E) tool was used. The Delphi method was executed in two rounds by three researchers to assess bias. RESULTS: Chronically critically ill patients with the immunosuppressive status have reduced levels of HLA-DR and ALC and elevated sPD-L1 and IL-10 levels. The results of the studies were rated at ‘high’ and ‘moderate’ risk of reporting bias. Their findings should be considered as low-quality results. CONCLUSIONS: Chronic critical illness is a poorly understood condition that periodically occurs in patients in the ICU. The immune status of chronically critically ill patients is a debatable issue, as the current data are insufficient to draw a definitive conclusion. Based on the systematic review, further prospective trials are required to study the immune status of chronically critically ill patients.

High Pretreatment Serum PD-L1 Levels Are Associated with Muscle Invasion and Shorter Survival in Upper Tract Urothelial Carcinoma.

Simple SummaryThis study aimed to assess the prognostic relevance of soluble serum PD-L1 in upper tract urothelial carcinoma (UTUC) patients who underwent surgical or systemic (chemo- or immune checkpoint inhibitor) therapy. We found that high preoperative sPD-L1 levels were correlated with higher pathological tumor stage, grade and the presence of metastasis. In addition, higher pretreatment serum PD-L1 concentrations were associated with shorter survival in both surgically and chemotherapy-treated UTUC patients. We detected a characteristic increase in serum PD-L1 levels in UTUC patients after 3 months of anti-PD-L1 therapy. Based on these results sPD-L1 is a promising prognostic biomarker in UTUC.Programmed death ligand-1 (PD-L1) is an immune checkpoint molecule and a widely used therapeutic target in urothelial cancer. Its circulating, soluble levels (sPD-L1) were recently suggested to be associated with the presence and prognosis of various malignancies but have not yet been investigated in upper tract urothelial carcinoma (UTUC). In this study, we assessed sPD-L1 levels in 97 prospectively collected serum samples from 61 UTUC patients who underwent radical nephroureterectomy (RNU), chemotherapy (CTX), or immune checkpoint inhibitor (ICI) therapy. In addition to pretreatment samples, postoperative and on-treatment sPD-L1 levels were determined in some patients by using ELISA. In the RNU group, elevated preoperative sPD-L1 was associated with a higher tumor grade (p = 0.019), stage (p < 0.001) and the presence of metastasis (p = 0.002). High sPD-L1 levels were significantly associated with worse survival in both the RNU and CTX cohorts. sPD-L1 levels were significantly elevated in postoperative samples (p = 0.011), while they remained unchanged during CTX. Interestingly, ICI treatment caused a strong, 25-fold increase in sPD-L1 (p < 0.001). Our results suggest that elevated preoperative sPD-L1 level is a predictor of higher pathological tumor stage and worse survival in UTUC, which therefore may help to optimize therapeutic decision-making. The observed characteristic sPD-L1 flare during immune checkpoint inhibitor therapy may have clinical significance.

Soluble programmed cell death-ligand 1 as a new potential biomarker associated with acute coronary syndrome.

BackgroundSoluble programmed cell death-ligand 1 (sPD-L1) has been well documented to activate immunosuppression and is considered an essential predictor of negative clinical outcomes for several malignances and inflammatory conditions. However, the clinical significance of sPD-L1 in the peripheral blood of patients with coronary artery disease (CAD) remains unclear. The aim of this study was to assess the correlations of sPD-L1 with clinical features in CAD patients and evaluate the diagnostic value of this protein in CAD.MethodsA total of 111 CAD patients and 97 healthy volunteers who served as healthy controls (HCs) were consecutively enrolled. Plasma levels of sPD-L1 were measured with an amplified enzyme-linked immunosorbent assay (ELISA), and hs-CRP was measured with a C-reactive protein assay kit. The levels of other inflammatory cytokines were assessed in 88 CAD patients and 47 HCs by a multiparameter immunoluminescence flow cytometry detection technique. A logistic regression model was used to assess the independent association of sPD-L1 with acute coronary syndrome (ACS). The correlation between sPD-L1 and inflammatory cytokines in ACS was also assessed.ResultsPlasma levels of sPD-L1 were significantly increased in CAD patients, especially those with ACS. Univariate logistic regression analysis revealed that sPD-L1 (OR: 3.382, 95% CI: 2.249–5.084, p < 0.001), BMI, hypertension, diabetes, dyslipidemia, previous MI, and the levels of HDL-C, LDL-C and hs-CRP were significantly associated with ACS. sPD-L1 (OR: 3.336, 95% CI: 1.084–6.167, p = 0.001) was found to be independently and significantly associated with ACS in the subsequent multivariable logistic regression analysis. Additionally, elevated plasma sPD-L1 levels were associated with increased interleukin-6 and interleukin-8 levels in ACS patients. Receiver operating characteristic (ROC) analysis showed that the AUC of sPD-L1 for diagnosing ACS was 0.778, with a sensitivity of 73.9% and a specificity of 73.4%, which was comparable with that of the inflammatory biomarker hs-CRP.ConclusionThe plasma sPD-L1 level reflects the severity of CAD, is associated with inflammatory responses and is a potential new biomarker for the diagnosis of ACS.

Overlapping but Disparate Inflammatory and Immunosuppressive Responses to SARS-CoV-2 and Bacterial Sepsis: An Immunological Time Course Analysis.

Both severe SARS-CoV-2 infections and bacterial sepsis exhibit an immunological dyscrasia and propensity for secondary infections. The nature of the immunological dyscrasias for these differing etiologies and their time course remain unclear. In this study, thirty hospitalized patients with SARS-CoV-2 infection were compared with ten critically ill patients with bacterial sepsis over 21 days, as well as ten healthy control subjects. Blood was sampled between days 1 and 21 after admission for targeted plasma biomarker analysis, cellular phenotyping, and leukocyte functional analysis via enzyme-linked immunospot assay. We found that circulating inflammatory markers were significantly higher early after bacterial sepsis compared with SARS-CoV-2. Both cohorts exhibited profound immune suppression through 21 days (suppressed HLA-DR expression, reduced mononuclear cell IFN-gamma production), and expanded numbers of myeloid-derived suppressor cells (MDSCs). In addition, MDSC expansion and ex vivo production of IFN-gamma and TNF-alpha were resolving over time in bacterial sepsis, whereas in SARS-CoV-2, immunosuppression and inflammation were accelerating. Despite less severe initial physiologic derangement, SARS-CoV-2 patients had similar incidence of secondary infections (23% vs 30%) as bacterial sepsis patients. Finally, COVID patients who developed secondary bacterial infections exhibited profound immunosuppression evident by elevated sPD-L1 and depressed HLA-DR. Although both bacterial sepsis and SARS-CoV-2 are associated with inflammation and immune suppression, their immune dyscrasia temporal patterns and clinical outcomes are different. SARS-CoV-2 patients had less severe early inflammation and organ dysfunction but had persistent inflammation and immunosuppression and suffered worse clinical outcomes, especially when SARS-CoV-2 infection was followed by secondary bacterial infection.

Prognostic Value of Soluble Programmed Cell Death Ligand-1 (sPD-L1) in Various Cancers: A Meta-analysis

The prognostic value of soluble programmed cell death ligand-1 (sPD-L1) in patients with cancer has been inconsistent across previous studies. This meta-analysis aimed to investigate the prognostic significance of sPD-L1 in human tumors. A comprehensive search of PubMed, Web of Science, Embase, and Cochrane databases from inception to January 6, 2020 was conducted. Studies of sPD-L1 measured by enzyme-linked immunosorbent assay (ELISA) that had available hazard ratios (HRs) for survival outcomes based on high or low sPD-L1 levels were included. The primary endpoint was long-term survival, namely, overall survival (OS), and the second endpoint was short-term survival, including progression-free survival (PFS), disease-free survival (DFS), recurrence-free survival (RFS), and cancer-specific survival (CSS). A total of 21 studies, with 2413 patients, were included in this meta-analysis. Elevated sPD-L1 was associated with worse OS [HR = 2.46, 95% confidence interval (CI) 1.74-3.49, P <0.001]. Moreover, high sPD-L1 was predictive of worse PFS/DFS/RFS/CSS (HR = 2.22, 95% CI 1.47-3.35, P <0.001). High sPD-L1 was consistently correlated with poor OS and PFS/DFS/RFS/CSS irrespective of study design, sample, and cut-off value of sPD-L1. However, there was non-significant correlation between sPD-L1 and sex, age, clinical stage, Eastern Cooperative Oncology Group Performance Status, tumor differentiation, or serum lactate dehydrogenase. This meta-analysis showed that sPD-L1 was correlated with poor prognosis in human tumors. In addition, sPD-L1 could be used as a predictive factor of inferior outcomes during multiple malignancy treatments.

Serum levels of soluble programmed death-1 (sPD-1) and soluble programmed death ligand 1(sPD-L1) in systemic lupus erythematosus: Association with activity and severity.

The programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an important host immunosuppression mechanism. Soluble PD-1 (sPD-1) and PD-L1 (sPD-L1) expression regulates co-inhibitory signals in autoimmune disorders. Here, we evaluated whether serum sPD-1 and sPD-L1 are involved in immune dysfunction and assessed its relationship with SLE. Blood samples were obtained from 130 patients with SLE and 44 healthy controls. Serum sPD-1 and sPD-L1 were tested by enzyme-linked immunosorbent assay (ELISA). Relevant immune parameters were analysed. Both serum sPD-1 and sPD-L1 were significantly higher in the SLE patients than in the controls. A series of severe disease clinical manifestations and laboratory features such as presence of decreased complement component 3, complement component 4 and SLEDAI >8 were associated with elevated sPD-1 and sPD-L1. Our study suggests that abnormal sPD-1 and sPD-L1 expression may be involved in the imbalance of immune regulation in SLE.

Soluble PD-L1 in NSCLC Patients Treated with Checkpoint Inhibitors and Its Correlation with Metabolic Parameters.

We investigated the role of soluble PD-L1 (sPD-L1) in non-small cell lung carcinoma (NSCLC) patients treated with immune checkpoint inhibitors (ICI) and analyzed its association with clinical outcomes and metabolic parameters by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT). Between July 2017 and May 2019, we enrolled 20 candidate patients of ICI therapy who had serum frozen samples and 18F-FDG PET/CT available, both at baseline and at the first response evaluation. This analysis is embedded into a larger prospective study (NCT03563482). Twelve out of 20 patients received nivolumab, one patient received combination of nivolumab and ipilimumab, whereas the others received pembrolizumab. Median sPD-L1 level at baseline was 27.22 pg/mL. We found a significant association between patients with elevated sPD-L1, above the median value, and high metabolic tumor burden, expressed by metabolic tumor volume (MTV, 115.3 vs. 35.5, p = 0.034) and total lesion glycolysis (TLG, 687 vs. 210.1, p = 0.049). At the first restaging after 7–8 weeks, median sPD-L1 levels significantly increased as compared to baseline median value (43.9 pg/mL, p = 0.017). No significant differences in response rates were detected, according to both morphological and metabolic response criteria. Likewise, no difference in survival outcomes were observed between low sPD-L1 and high sPD-L1 patients. The increase of sPD-L1 concentrations during ICI treatment may reflect the expansion of tumor volume and the tumor lysis. Moreover, it is supposed that sPD-L1 has its own biological action, either by reducing membrane PD-1 sites available for nivolumab or by inducing lymphocytes exhaustion after binding their membrane PD-1. Further, larger studies are needed to confirm our preliminary results on the role of sPD-L1 during ICI therapy.

738P - Soluble programmed death-ligand 1 indicate poor prognosis in hepatocellular carcinoma patients undergoing transcatheter arterial chemoembolization

BackgroundSoluble programmed death-ligand 1 (sPD-L1) is associated with hepatocellular carcinoma (HCC) prognosis after resection or radiotherapy. However, its value in patients who received transcatheter arterial chemoembolization (TACE) remains unclear. The present study aimed to determine the prognostic significance of sPD-L1 in TACE subgroup. Methods114 HCC patients with hepatitis B virus (HBV)-background who received TACE from 2012 to 2013 were recruited. sPD-L1 levels were determined by enzyme-linked immunosorbent assay. We evaluated prognoses according to mRESIST criteria and analyzed prognostic values by Cox regression and Kaplan-Meier analysis. We further evaluated correlations between sPD-L1 and systemic inflammation index (SII), soluble interleukin-2 receptor (sIL-2R), IL-10, hepatitis B virus (HBV)-DNA loads, and C-reactive protein. ResultsSignificantly elevated sPD-L1 levels were found in patients who developed HCC progression (P=0.002) and death (P<0.001). Patients with higher pre-treatment sPD-L1 levels had a significantly shorter time to progression (10.50 vs. 18.25 months, P=0.001) and decreased overall survival (16.50 vs. 28.50 months, P=0.003). In low-recurrence-risk subgroups, sPD-L1 levels retained prognostic value (P<0.050). Importantly, multivariate regression confirmed that pre-treatment sPD-L1 level was an independent predictor for both progression [hazard ratio (HR) 1.82; P=0.032] and survival (HR 1.84; P=0.009). Moreover, sPD-L1 levels positively correlated with SII (r=0.284, P=0.002), sIL-2R (r=0.239, P=0.010), IL-10 (r=0.283, P=0.002), HBV-DNA loads (r=0.229, P=0.014), and CRP (r=0.237, P=0.011). ConclusionssPD-L1 level is a prognostic indicator of poor outcomes after TACE. High sPD-L1 indicated increased immune activation in an immunosuppressive environment that hindered anti-tumor response activity. Lowering sPD-L1 levels may provide a novel avenue for preventing HCC progression post-TACE. Legal entity responsible for the studyThe authors. FundingThe National Natural Science Foundation of China (87172263 and 81572064) and Key Developing Disciplines of Shanghai Municipal Commission of Health and Family Planning (2015ZB0201). DisclosureAll authors have declared no conflicts of interest.

Long-term Host Immune Response Trajectories Among Hospitalized Patients With Sepsis

Long-term immune sequelae after sepsis are poorly understood. To assess whether abnormalities in the host immune response during hospitalization for sepsis persist after discharge. This prospective, multicenter cohort study enrolled and followed up for 1 year adults who survived a hospitalization for sepsis from January 10, 2012, to May 25, 2017, at 12 US hospitals. Circulating levels of inflammation (interleukin 6 and high-sensitivity C-reactive protein [hs-CRP]), immunosuppression (soluble programmed death ligand 1 [sPD-L1]), hemostasis (plasminogen activator inhibitor 1 and D-dimer), endothelial dysfunction (E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1), and oxidative stress biomarkers were measured at 5 time points during and after hospitalization for sepsis for 1 year. Individual biomarker trajectories and patterns of trajectories across biomarkers (phenotypes) were identified. Outcomes were adjudicated centrally and included all-cause and cause-specific readmissions and mortality. A total of 483 patients (mean [SD] age, 60.5 [15.2] years; 265 [54.9%] male) who survived hospitalization for sepsis were included in the study. A total of 376 patients (77.8%) had at least 1 chronic disease, and their mean (SD) Sequential Organ Failure Assessment score was 4.2 (3.0). Readmissions were common (485 readmissions in 205 patients [42.5%]), and 43 patients (8.9%) died by 3 months, 56 patients (11.6%) died by 6 months, and 85 patients (17.6%) died by 12 months. Elevated hs-CRP levels were observed in 23 patients (25.8%) at 3 months, 26 patients (30.2%) at 6 months, and 23 patients (25.6%) at 12 months, and elevated sPD-L1 levels were observed in 45 patients (46.4%) at 3 months, 40 patients (44.9%) at 6 months, and 44 patients (49.4%) at 12 months. Two common phenotypes were identified based on hs-CRP and sPDL1 trajectories: high hs-CRP and sPDL1 levels (hyperinflammation and immunosuppression phenotype [326 of 477 (68.3%)]) and normal hs-CRP and sPDL1 levels (normal phenotype [143 of 477 (30.0%)]). These phenotypes had similar clinical characteristics and clinical course during hospitalization for sepsis. Compared with normal phenotype, those with the hyperinflammation and immunosuppression phenotype had higher 1-year mortality (odds ratio, 8.26; 95% CI, 3.45-21.69; P < .001), 6-month all-cause readmission or mortality (hazard ratio [HR], 1.53; 95% CI, 1.10-2.13; P = .01), and 6-month readmission or mortality attributable to cardiovascular disease (HR, 5.07; 95% CI, 1.18-21.84; P = .02) or cancer (HR, 5.15; 95% CI, 1.25-21.18; P = .02). These associations were adjusted for demographic characteristics, chronic diseases, illness severity, organ support, and infection site during sepsis hospitalization and were robust in sensitivity analyses. In this study, persistent elevation of inflammation and immunosuppression biomarkers occurred in two-thirds of patients who survived a hospitalization for sepsis and was associated with worse long-term outcomes.

Elevated levels of soluble PD-L1 are associated with reduced recurrence in papillary thyroid cancer

To date, no research evaluating the predictive capabilities of soluble programmed cell death-ligand 1 (sPD-L1) in thyroid cancer patients has been performed. We aimed to investigate the prognostic significance of sPD-L1 expression in papillary thyroid cancer (PTC) and to evaluate the association between sPD-L1 levels with tumoural PD-L1 expression and patient outcomes. Pre-treatment levels of serum and plasma sPD-L1 were measured by ELISA in 101 PTC patients. Tissue microarrays were stained with an anti-PD-L1 antibody, clone SP263 (Ventana). The median serum sPD-L1 concentration in PTC patients was significantly higher compared to healthy controls (P = 0.028). An increased incidence of extrathyroidal extension was significantly associated with an elevated serum sPD-L1 level (P = 0.015). Patients with high serum sPD-L1 levels had significantly shorter median disease-free survival (DFS) as compared to those with low sPD-L1 levels (P = 0.011). Following multivariate analysis, serum sPD-L1 was the only statistically significant predictor for DFS. Patients with both positive serum and tumoural PD-L1 expression had a significantly shorter DFS than those in any other subgroup (P = 0.007). Our study is the first to confirm that sPD-L1 concentration is significantly associated with patient outcome in PTC. Soluble PD-L1 may provide clinicians with a non-invasive biomarker that can lessen dependence on tissue biopsies and diagnose aggressive thyroid cancers at a more treatable stage.

Soluble programmed death-ligand 1 are highly expressed in peripheral T-cell lymphoma: a biomarker for prognosis

ABSTRACTPurposeTo investigate the role of soluble programmed cell death ligand 1 (sPD-L1) protein in plasma of patients with Peripheral T-cell lymphoma (PTCL).MethodsIn total, 80 patients with newly diagnosed PTCL and 75 healthy controls were enrolled. Levels of sPD-L1 were measured by ELISA at diagnosis and after 3–8 courses of chemotherapy. The expression of PD-L1 in tumor tissues from nine PTCL patients was also detected.ResultssPD-L1 was higher in PTCL patients at diagnosis compared to healthy subjects (P < 0.0001). Patients in the intermediate/high-risk disease group had a higher level of sPD-L1 than patients in the low-risk group (P = 0.0003). Elevated sPD-L1 (≥176.30 pg/ml) was the only biomarker for PTCL that retain statistical significance in multivariate analysis. Patients in the low-risk group with sPD-L1 ≥ 176.30 pg/ml had an adverse prognosis. Histological analysis showed that the expression of PD-L1 in tissues was positively correlated with sPD-L1 levels in plasma (Spearman = 0.9177, P = 0.0013).ConclusionssPD-L1 is a sensitive biomarker predicting clinical outcomes in PTCL.

Soluble PD-L1 Expression in Circulation as a Predictive Marker for Recurrence and Prognosis in Gastric Cancer: Direct Comparison of the Clinical Burden Between Tissue and Serum PD-L1 Expression.

This study assessed programmed cell death ligand 1 (PD-L1) expression in primary tissues and soluble PD-L1 (sPD-L1) concentration in matched preoperative serum in gastric cancer (GC) patients to perform direct comparison between tissue and serum PD-L1 expression and to clarify the prognostic implication in GC. The study enrolled 180 GC patients who underwent surgery for GC at the authors' institution. The study evaluated tissue PD-L1 expression using immunohistochemistry and quantified sPD-L1 concentration in preoperative serum using enzyme-linked immunosorbent assay in GC patients. The findings showed that PD-L1 was overexpressed in GC tissues compared with normal mucosa. Tissue PD-L1 expression was significantly higher in the GC patients with advanced T stage, presence of lympho-vascular invasion, lymph node metastasis, and peritoneal metastasis. Furthermore, elevated tissue PD-L1 expression was significantly associated with poor prognosis for overall survival (OS) and disease-free survival (DFS). Serum sPD-L1 was significantly higher in the GC patients than in the healthy volunteers. Although serum sPD-L1 was not correlated with any clinicopathologic factors, the patients with high serum sPD-L1 showed poorer OS and DFS than those with low sPD-L1. Multivariate analyses showed that both elevated tissue PD-L1 and serum sPD-L1 were independent prognostic factors for poor OS [tissue PD-L1: hazard ratio (HR), 4.28; 95% confidence interval (CI), 1.43-12.8; P = 0.0094 vs. serum sPD-L1: HR, 11.2; 95% CI, 3.44-36.7; P = 0.0001] and poor DFS (tissue PD-L1: HR, 6.96; 95% CI, 2.48-19.6; P = 0.0002 vs. serum sPD-L1: HR, 8.7; 95% CI, 3.16-23.9; P < 0.0001) for the GC patients. Furthermore, infiltrative CD8- and Foxp3-positive T cells were significantly increased in the GC patients with elevated tissue PD-L1 expression. Both serum sPD-L1 and tissue PD-L1 expression may serve as predictive biomarkers for recurrence and prognosis in GC patients.

Validation of Elevated Blood Soluble PD-L1 As an Independent Prognostic Marker in Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL)

Background. Recent clinical trials based on immunotherapies targeting the PD-1/PD-L1 pathway have shown striking durable responses in a subset of patients with solid cancers. The Programmed death 1 (PD-1) protein is a key immune checkpoint inhibitor expressed by activated T cells. Its ligand, PD-L1, was reported highly expressed by tumor cells in some diffuse large B-cell lymphomas (DLBCL) of non-Germinal Center phenotype. We recently reported on the French multicenter GOELAMS075 trial that pre-treatment soluble PD-L1 (sPD-L1) in plasma was elevated in DLBCL patients compared to controls, and that elevated sPD-L1 was associated with inferior overall survival (OS), independent of the International Prognostic Index (IPI) and other clinical factors (Rossille et al., Leukemia 2014). Here, we replicate and extend these findings in two independent studies from Australia and the US.Methods. The protein expression of sPD-L1 was evaluated using a commercial ELISA kit. The French discovery cohort consisted of 288 adults with newly diagnosed aggressive DLBCL, age 18 to 60 years, and treated with R-CHOP or high dose chemotherapy plus rituximab followed by autologous stem cell support (clinicaltrials.gov: NCT00561379); there were also 60 controls. The Australian study consisted of 51 DLBCL patients age 18 to 71 years, all stages, treated with R-CHOP14, along with 57 controls. The US study was an observational cohort from the Iowa/Mayo Lymphoma SPORE and consisted of 225 DLBCLs, age 19 to 92 years, all stages, treated with immunochemotherapy, along with 98 controls. Plasma samples were collected pre-treatment using EDTA tubes for the Australian and the US cohorts, BDª P100 tubes for the French cohort. sPD-L1 expression was measured in Rennes, France (French & US samples) and in Brisbane, Australia (Australian samples).The Kaplan-Meier method and Cox regression were used to model the association of sPD-L1 with OS. The 95th percentile of the sPD-L1 levels in each matched control group was used as the cutoff point to define elevated sPD-L1 levels.Results. Replicating the French findings, sPD-L1 levels were significantly higher for DLBCL patients compared to controls in both the US (P<0.0001) and Australian (P<0.0001) studies (Figure 1). The odds ratios for elevated sPD-L1 among patients compared to controls were 10.7 (95% CI 3.3-22.0), 8.9 (95% CI 3.1-25.3) and 12.6 (95% CI 2.7-28.0) for the French, US and Australian studies, respectively. In the French cohort, elevated sPD-L1 levels were associated with inferior OS (Hazard Ratio (HR)=2.05; 95% CI 1.18-3.57), and this was replicated in the US cohort (HR=1.71; 95% CI 0.97-3.01) (Figure 2). Due to the similarity of the results, we next pooled the French and US cohorts to increase power for multivariate and subset analyses. The median age at diagnosis of the 513 patients was 54 years; 29% were more than 60 years old; 69% of the patients had stage III-IV disease; 56% were IPI intermediate-risk and 9% were IPI high-risk patients. The median follow-up was 48 months (range, 0.5-126) overall, and 66 months for the patients still alive; there were 102 deaths. Using a cutpoint of 1729 pg/mL from the combined studies, patients with elevated sPD-L1 had inferior OS compared to patients without elevated sPD-L1, with 3-year OS rates estimated at 78% (95% CI 71.8-84.9) vs. 87.8% (95%CI 84.5-91.4) (P<0.01). In multivariate analysis, elevated sPD-L1 (HR=1.75; 95%CI 1.16-2.64), age (HR=1.03; 95%CI 1.02-1.05), high-risk IPI score (HR=3.71; 95%CI 1.91-7.21) and ALC ² 1 G/L (HR=2.19; 95%CI 1.44-3.33) were all significant at P<0.01. In analyses stratified by IPI, the 3-year OS rates among high-risk patients (IPI 4-5) was 40.9% (95% CI 23.6-71.0) for elevated sPD-L1 vs. 82.1% (95% CI 69.1-97.6) for not elevated sPD-L1 (P<0.01). There was no association of sPD-L1 with 3-year OS among low risk (IPI 0-1) or intermediate-risk (IPI 2-3) patients.Conclusion. We confirmed that sPD-L1 levels are higher in pre-treatment plasma samples of newly diagnosed DLBCL patients compared to controls, and that elevated levels of sPD-L1 are associated with inferior OS in DLBCL patients treated with immunochemotherapy, and this is independent of IPI and other clinical factors. Among high risk patients, we identified a subgroup with less than 50% survival. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-Cell lymphoma: results from a French multicenter clinical trial.

The dosage of soluble programmed cell death ligand 1 (sPD-L1) protein in the blood of adults with cancer has never been performed in a prospective patient cohort. We evaluated the clinical impact of sPD-L1 level measured at the time of diagnosis for newly diagnosed diffuse large B-cell lymphoma (DLBCL). Soluble PD-L1 was measured in the plasma of 288 patients enrolled in a multicenter, randomized phase III trial that compared R-high-dose chemotherapy with R-CHOP. The median follow-up was 41.4 months. A cutoff of 1.52 ng/ml of PD-L1 level was determined and related to overall survival (OS). Patients with elevated sPD-L1 experienced a poorer prognosis with a 3-year OS of 76% versus 89% (P<0.001). Considering clinical characteristics, the multivariate analysis retained this biomarker besides bone marrow involvement and abnormal lymphocyte-monocyte score as independently related to poor outcome. sPD-L1 was detectable in the plasma and not in the serum, found elevated in patients at diagnosis compared with healthy subjects and its level dropped back to normal value after CR. The intention-to-treat analysis showed that elevated sPD-L1 was associated with a poorer prognosis for patients randomized within the R-CHOP arm (P<0.001). Plasma PD-L1 protein is a potent predicting biomarker in DLBCL and may indicate usefulness of alternative therapeutic strategies using PD-1 axis inhibitors.

Blood Soluble PD-L1 Protein In Aggressive Diffuse Large B-Cell Lymphoma Impacts patient's Overall Survival

PurposeProgrammed death 1 (PD-1) protein is a key immune-checkpoint receptor expressed by activated T cells and it mediates immunosuppression. It has been recently shown that the blockade of PD-1 or its ligand, PD-L1, by monoclonal antibodies may lead to significant antitumor effects. In diffuse large B-cell lymphoma PD-L1 has been reported expressed by tumor cells and PD-1 by tumor-associated T cells. The dosage of soluble programmed death ligand 1 (sPD-L1) protein in the blood of adults with cancer has never been performed during a clinical trial. We evaluated the clinical impact of PD-L1 level measured at the time of diagnosis for newly diagnosed aggressive diffuse large B-cell lymphomas. MethodsTranslating a previous study (NEJMed2004; 350: 1287) in the rituximab era, the Groupe Ouest-Est des Leucemies et des Autres Maladies du Sang (GOELAMS) 075 study is a multicenter randomized trial in which adults 18 to 60 years old with untreated histologically proved CD20 positive diffuse large B-cell lymphoma were randomly assigned to receive 8 courses of R-CHOP or, high-dose chemotherapy associated to rituximab followed by autologous stem cell support (clinicaltrials.gov: NCT00561379). Patients were required to have an Ann Arbor stage of I or II with bulk greater or equal to 7 cm or, III or IV with 0 to 3 adverse prognostic factors as defined by the age-adjusted International Prognostic Index. The population of interest consisted of 288 of the 340 consecutively enrolled patients with available plasma collected at the time of diagnosis before any treatment. Soluble PD-L1 was measured using an ELISA assay. The median follow-up was 41.4 months. ResultssPD-L1 levels were found significantly increased in the plasma collected at diagnosis for patients compared to healthy -gender and age matched- subjects' levels (P<0.0001). The optimal cut-off point for PD-L1 measured at diagnosis was found to be equal to 1.52 ng/mL. Eighty-nine (30.9%) patients had a PD-L1 level greater than the cut-off point as compared to two (3%) controls. The high-level sPD-L1 group was significantly associated with bone marrow involvement, more than one extranodal localization and, 2-4 performance ECOG status. None of the other patients' characteristics, including the assigned arms of randomization and, the positive vs. negative FDG-PET scan response at the intermediate evaluation, was associated with high PD-L1 level. The PD-L1 immunohistochemical analysis showed that 55 out of the 73 interpretable tissue microarrays presented at least 5% of PD-L1-positive tumor cells. No association was found between sPD-L1 and tumor PD-L1 expressions (p=0.5). The 73 patients were representative of our 288 patients' cohort, with significantly decreased overall survival for patients with a high level of sPD-L1 compared to those with low sPD-L1 levels (64.6 vs. 86.7%, P=0.007). Cell-of-origin analysis using Hans's criteria on the tissue microarrays did not shown any correlation between elevated sPD-L1 and GC or non-GC origin.Patients with elevated PD-L1 experienced a poor prognosis with a three-year overall survival of 76 vs. 89 percent (P<0.001).There was no difference of overall survival rates between the two arms of treatment. Univariate analysis identified age greater than 50 years old, high-intermediate and, high age-adjusted International Prognostic Index score, bone marrow involvement, more than one extranodal localization, Ann Arbor stage after FDG-PET scan of III or IV, abnormal lymphocyte-monocyte score and, high level of sPD-L1 as factors associated with poor survival. High level of sPD-L1, bone marrow involvement and, abnormal lymphocyte-monocyte score were found after multivariate analysis to be the only factors remaining significant after adjustment with a P-value <0.05. Soluble PD-L1 was detectable in the plasma and not in the serum, found elevated in lymphoma patients at diagnosis compared to healthy subjects and its level dropped back to normal value for patients in complete remission. The intention-to-treat analysis showed that elevated PD-L1 was associated with a poorer prognosis for patients randomized within the R-CHOP arm (P<0.001). [Display omitted] ConclusionSoluble PD-L1 protein expression in peripheral blood at the time of diagnosis is a potent predicting biomarker in diffuse large B-cell lymphoma and may indicate usefulness of alternative therapeutic strategies using PD1 axis inhibitors. Disclosures:Fest:Roche SA France: Research Funding.