Serum sPD-L1 Levels Research Articles

Effect of Follicular T Helper and T Helper 17 Cells-Related Molecules on Disease Severity in Patients with Myasthenia Gravis.

Contribution of T helper 1 and 2 cells-related cytokines to pathogenesis of myasthenia gravis (MG) is well known. Recently, the contribution of follicular T helper (Tfh) and T helper 17 cells-related molecules to the pathogenesis has gained importance. In this study, we aimed to evaluate the changes in Tfh- and Th17-related molecules before and after rescue therapy in patients with myasthenic crisis (cMG) and to reveal the molecular differences between stable MG and cMG patients. Patients with stable generalized MG (gMG) and cMG were classified according to Myasthenia Gravis Foundation of America (MGFA) classification. Serum samples were collected from cMG patients both before and after rescue therapy (plasmapheresis or intravenous immunoglobulin [IVIg]). Serum levels of Tfh- and selected Th17-related molecules (IL-22, IL-17A, CXCL13, sPD-L1, sICOSLG, and sCD40L) were analyzed by commercial ELISA kits. Twelve cMG (6 for IVIg, 6 for plasmapheresis) and 10 gMG patients were included in the study. A decrease in serum sPD-L1 and CXCL13 levels was observed in cMG patients after treatment, regardless of the treatment modality (p < 0.05). In contrast, serum sICOSLG levels decreased only in patients treated with IVIg (p < 0.05) and serum IL-22 levels increased in patients receiving plasmapheresis (p < 0.05). cMG patients had higher serum IL-17A levels compared to stable patients (p < 0.001) and its level was positively correlated with disease severity (r = 0.678, p = 0.001). Our results confirm the contribution of Tfh- and Th17-related cell pathways to MG pathogenesis. Both IVIg and plasmapheresis appear to be effective in reducing Tfh- and Th17-related cytokine/molecule levels in cMG patients. Increased serum IL-17A levels may contribute to disease severity.

Serum sPD-1 and sPD-L1 as predictive biomarkers for HBsAg clearance in HBeAg-negative CHB patients undergoing IFN-based therapy.

For chronic hepatitis B (CHB) patients, there is still a need to improve hepatitis B surface antigen (HBsAg) clearance rates. This study aimed to assess the predictive effectiveness of soluble programmed cell death-1 (sPD-1) and soluble programmed cell death ligand-1 (sPD-L1) for HBsAg clearance in HBeAg-negative CHB patients undergoing peginterferon (Peg-IFN)-based antiviral treatment. This study encompassed 280 patients undergoing treatment with Peg-IFNα. Serum levels of sPD-1 and sPD-L1 were measured using ELISA kits at baseline, as well as at 12, 24 and 48 weeks. The primary endpoint of the study was the determination of HBsAg clearance at 48 weeks. Logistic regression analysis was employed to identify predictors of HBsAg clearance. The clearance group demonstrated significantly lower serum sPD-L1 levels compared to the non-clearance group. While both groups exhibited an increase in sPD-1 levels, only the clearance group showed a rise in sPD-L1 levels. Multivariate analysis identified sPD-L1 increase at 24 weeks, and HBsAg decline at 24 weeks as predictors for HBsAg clearance at 48 weeks. The combined use of these indicators showed a predictive performance for HBsAg clearance with an AUROC of 0.907 (95% CI: 0.861-0.953, p < 0.001). The study revealed an inverse relationship between the trends of sPD-1/sPD-L1 and HBsAg clearance during combined IFN and NAs treatment. Moreover, the magnitude of HBsAg reduction and sPD-L1 increase emerged as significant predictors for HBsAg clearance.

Soluble PD-L1 predicts tumor response and immune-related adverse events in patients with advanced melanoma treated with anti-PD-1 antibodies.

Immune checkpoint inhibitors (ICIs) bring prognostic benefits to patients with malignancies. However, there is a substantial number of patients whose lesions are not improved by ICIs. In addition, ICIs may cause immune-related adverse events (irAEs), which could lead to an unfavorable prognosis with fatal consequences. Therefore, we conducted a retrospective study to evaluate the utility of circulating sPD-L1 (soluble programmed cell death 1 ligand 1) as a biomarker in patients with advanced melanoma treated with anti-PD-1 (programmed cell death 1 protein) antibodies. Sera from 31 consecutive patients were prospectively collected before and after anti-PD-1 antibody treatment and the serum level of sPD-L1 was evaluated. We found that high sPD-L1 levels before treatment were associated with better prognosis, and this association was observed only in patients with a low tumor burden. We also found that sPD-L1 levels were elevated in patients who developed severe irAEs after treatment, and the patients with severe irAEs had significantly higher fluctuations in sPD-L1 (delta sPD-L1) than those without severe irAEs. Our study suggests that serum sPD-L1 level is a useful biomarker to predict tumor response and irAE development in patients with advanced melanoma treated with anti-PD-1 antibodies.

Decreased serum soluble programmed cell death ligand-1 level as a potential biomarker for missed miscarriage.

Can maternal serum levels of soluble programmed cell death-1 (sPD-1) and its ligand (sPD-L1) serve as biomarkers for missed miscarriage (MM)? Serum sPD-L1 levels are significantly decreased in MM patients and may serve as a potential predictive biomarker for miscarriage. Programmed cell death-1 (PD-1) and its ligand (PD-L1) comprise important immune inhibitory checkpoint signaling to maintain pregnancy. Their soluble forms are detectable in human circulation and are associated with immunosuppression. Three independent cohorts attending tertiary referral hospitals were studied. The first (discovery) cohort was cross-sectional and included MM patients and healthy pregnant (HP) women matched on BMI. The second validation cohort contained MM patients and women with legally induced abortion (IA). The third prospective observational study recruited subjects requiring IVF treatment. In the discovery cohort, we enrolled 108 MM patients and 115 HP women who had a full-term pregnancy at 6-14 weeks of gestation. In the validation cohort, we recruited 25 MM patients and 25 women with IA. Blood samples were collected at the first prenatal visit for HP women or on the day of dilatation and curettage surgery (D&C) for MM and IA subjects to determine serum sPD-1 and sPD-L1 levels. Placenta samples were harvested during the D&C within the validation cohort to measure gene and protein expression. The prospective cohort collected serial blood samples weekly from 75 volunteers with embryo transfer (ET) after IVF. Circulating sPD-L1 levels were reduced by 50% in patients with MM (55.7 ± 16.04 pg/ml) compared to HP controls (106.7 ± 58.46 pg/ml, P < 0.001) and the difference remained significant after adjusting for maternal age and gestational age, whereas no significant differences in sPD-1 level were observed. Likewise, serum sPD-L1 was lower in MM patients than in IA subjects and accompanied by downregulated PD-L1-related gene expression levels in the placenta. In the IVF cohort, applying the changing rate of sPD-L1 level after ET achieved a predictive performance for miscarriage with receiver operating characteristics = 0.73 (95% CI: 0.57-0.88, P < 0.01). The study was mainly confined to East Asian pregnant women. Further large prospective pregnancy cohorts are required to validate the predictive performance of sPD-L1 on miscarriage. Reduced circulating sPD-L1 level and downregulated placental PD-L1 expression in miscarriage indicate that dysfunction in PD-L1 signals is a potential underlying mechanism for pregnancy loss. Our findings further extend the importance of the PD-L1 axis in pregnancy maintenance in early pregnancy. This study was financially supported by grants from the Subject Innovation Team of Shaanxi University of Chinese Medicine (2019-Y502), General Research Fund (14122021), and Key Laboratory of Model Animal Phenotyping and Basic Research in Metabolic Diseases (2018KSYS003). The authors declare that they have no competing interests to be disclosed. N/A.

Serum sPD-L1 levels are elevated in patients with viral diseases, bacterial sepsis or in patients with impaired renal function compared to healthy blood donors.

Immune checkpoints play an important role in maintaining the balance of the immune system and in the development of autoimmune diseases. A central checkpoint molecule is the programmed cell death protein 1 (PD-1, CD279) which is typically located on the surface of Tcells. Its primary ligand PD-L1 is expressed on antigen presenting cells and on cancer cells. Several variants of PD-L1 exist, among these soluble molecules (sPD-L1) present in serum atlow concentrations. sPD-L1 was found elevated in cancer andseveral other diseases. sPD-L1 in infectious diseases has received relatively little attention so far and is therefore subject of this study. sPD-L1 serum levels were determined in 170 patients with viral infections (influenza, varicella, measles, Dengue fever, SARS-CoV2) or bacterial sepsis by ELISA and compared to the levels obtained in 11 healthy controls. Patients with viral infections and bacterial sepsis generally show significantly higher sPD-L1 serum levels compared to healthy donors, except for varicella samples where results do not reach significance. sPD-L1 is increased in patients with impaired renal function compared to those with normal renal function, and sPD-L1 correlates significantly with serum creatinine. Among sepsis patients with normal renal function, sPD-L1 serum levels are significantly higher in Gram-negative sepsis compared to Gram-positive sepsis. In addition, in sepsis patients with impaired renal function, sPD-L1 correlates positively with ferritin and negatively with transferrin. sPD-L1 serum levels are significantly elevated in patients with sepsis, influenza, mesasles, Dengue fever or SARS-CoV2. Highest levels are detectable in patients with measles and Dengue fever. Also impaired renal function causes an increase in levels of sPD-L1. As a consequence, renal function has to be taken into account in the interpretation of sPD-L1 levels in patients.

P-478 The decreases in serum soluble programmed cell death ligand −1 level are associated with missed miscarriage in humans

Abstract Study question The perturbations in serum levels of soluble forms of programmed cell death-1 (sPD-1) and its ligand (sPD-L1) in missed miscarriage (MM) are unknown. Summary answer Dysfunction in PD-L1 signal has been demonstrated in MM as evidenced by a lower circulating sPD-L1 level and declined expressions of PD-L1 in placenta. What is known already Programmed cell death-1 (PD-1) and its ligand (PD-L1) comprise important immune inhibitory checkpoint signaling to maintain pregnancy. During pregnancy, PD-L1 is highly expressed in the trophoblasts of the placenta. The reduced placental PD-L1 expression is associated with the risk of miscarriage. Therefore, disturbance of PD-1/PD-L1 axis in the fetomaternal interface is susceptible to be an important pathogenesis for pregnancy loss. Interestingly, the soluble form of these immune checkpoint molecules is detectable and associated with immunosuppression, it raises the diagnostic potential to monitor their level to monitor pregnancy health. Study design, size, duration In the discovery cohort, we enrolled 108 patients with MM and 115 body mass index (BMI)-matched, healthy women with a full-term pregnancy at 6 to 13 weeks of gestation. Another cohort of 25 MM patients and 25 subjects with induced abortion was recruited for validation. Participants/materials, setting, methods Blood samples were collected at the first prenatal visit for HP women or on the day of dilatation and curettage surgery (D&amp;C) for subjects with MM or IA to measure serum sPD-1 and sPD-L1 levels. Placenta samples were harvested during the D&amp;C within cohort 2 to examine related gene and protein expression. Main results and the role of chance Our results showed that circulating sPD-L1 levels were reduced by 50% in patients with MM (55.71 ± 1.54 pg/mL) compared to HP controls (107.27 ± 5.48 pg/mL, P&amp;lt;0.001) and remained significant after adjusting for maternal age and gestational age, whereas no significant differences in sPD-1 were observed between the two groups. Applying serum sPD-L1 levels achieved an area under the receiver operating characteristics curve (AUROC) of 0.83 (95% CI: 0.77 to 0.88, P&amp;lt;0.001) with the optimal cut-off value of 81.52 pg/ml to detect MM. Our data in the validation cohort further demonstrated that sPD-L1 was lower in MM patients relative to IA subjects. Likewise, placental PD-L1-related gene expressions were downregulated at both mRNA and protein levels in miscarriage samples relative to samples in IA groups and were positively associated with sPD-L1 levels in maternal circulation Limitations, reasons for caution This study was conducted in East Asian women, further studies are required for the evaluation of the serum PD-1 and sPD-L1 levels in different ethnic groups. Secondly, due to the cross-sectional nature of the study design, whether the sPD-L1 levels could utilize as a predictive biomarker is questioned. Wider implications of the findings The maternal serum sPD-L1 level has the potential to be a diagnostic aid for pregnancy maintenance. Moreover, insufficient PD-L1 expression in the feto-maternal interface may act as one of the potential pathogenic events to trigger early pregnancy loss. Trial registration number not applicable

Significance of soluble PD-L1 in patients with chronic hepatitis B and hepatitis C

Objective: The programmed death receptor 1/programmed death ligand 1 (PD-1/PD-L1) pathway can negatively regulate the immune response of the body, and serum soluble PD-L1 (sPD-L1) can reflect the expression level of PD-L1. This study aims to compare the expressional differences of sPD-L1 in serum between patients with chronic hepatitis B (CHB) and C (CHC) and further explore the factors influencing the clinical cure of CHB. Methods: 60 cases with CHB, 40 cases with CHC, and 60 healthy controls were selected. Serum levels of sPD-L1 were detected using an ELISA kit. The relationship between sPD-L1 levels and viral load, liver injury indicators, and others was analyzed in CHB and CHC patients. According to the distribution type of the data, a one-way ANOVA or Kruskal Wallis test as well as Pearson's correlation or Spearman's rank correlation analysis were performed. A difference of P<0.05 was considered statistically significant. Results: The serum sPD-L1 levels were significantly higher in CHB patients (414.6 ± 214.9) pg/ml than those in CHC patients (58.9 ± 122.1) pg/ml and the healthy control group (66.27 ± 24.43) pg/ml, and there was no statistically significant difference in serum sPD-L1 between CHC patients and the healthy control group. Further grouping and correlation analysis showed that the level of serum sPD-L1 was positively correlated with the content of HBsAg in CHB patients but not with HBV DNA, alanine transaminase, albumin, and other liver injury indicators. Additionally, there was no correlation between serum sPD-L1 levels, HCV RNA, and liver injury indicators in CHC patients. Conclusion: The serum sPD-L1 levels are significantly higher in CHB patients than those in the healthy control group and the CHC group, and there is a positive correlation between sPD-L1 levels and HBsAg. The persistent presence of HBsAg is an important mechanism for the activity of the PD-1/PD-L1 pathway, indicating that the activity of the PD-1/PD-L1 pathway may be an important factor that cannot be clinically cured in CHB as in CHC.

Soluble Programmed Cell Death Ligand-1 (sPD-L1) Levels in Various Cancer Types and Normal Populations.

To date, PD-L1 expression in tumor tissue, assessed by immunohistochemical stain, is clinically applicable as a predictive companion biomarker for PD-1/PD-L1 inhibitor which has been highlighted over the past several years. Before blood-based sPD-L1 enters clinical use, it is critical to establish the reference range. This study was designed to investigate soluble sPD-L1 levels in various cancer patients and normal population. For the detection of sPD-L1, 4 cancer groups (hepatocellular carcinoma, lung cancer, bladder cancer, gastric cancer) and healthy volunteers' samples were analyzed using an ELISA kit. Using a receiver operating characteristic curve, optimal sPD-L1 cutoff levels were determined. The mean serum sPD-L1 level of the normal population was 59.97 pg/mL (range; 23.780 - 115.2 pg/mL). In various cancer types, serum sPD-L1 levels ranged from 38.696 pg/mL to 228.77 pg/mL, and cutoff values under AUC ranged from 60.307 pg/mL to 64.371 pg/mL. sPD-L1 can be used as a screening biomarker in various cancer patients referring to optimal cutoff levels suggested.

High Serum sPD-L1 Level Predicts Poor Outcome in Hepatocellular Carcinoma Patients Treated with Radiotherapy

<h3>Purpose/Objective(s)</h3> To determine the clinical significance of serum soluble (s)PD-1 and sPD-L1 in hepatocellular carcinoma (HCC) received radiotherapy (RT). <h3>Materials/Methods</h3> In cohort 1, 144 HCC patients treated with liver RT were obtained from a prospectively collected database. Blood samples were collected 1 day before and 2 weeks after RT. In cohort 2, formalin-fixed paraffin-embedded samples were obtained from 46 patients with HCC, among whom 23 received preoperative RT and the other 23 received direct surgery. The relationship of sPD-1/sPD-L1 in serum or PD-L1 expression in tumor tissues and clinicopathological features were evaluated. <h3>Results</h3> In cohort 1, patients with tumor thrombosis (p = 0.01) and advanced stage (p = 0.00) had significantly higher serum sPD-L1 concentrations. Higher sPD-L1 level was negative predictor of progression-free survival (PFS) (HR = 1.53, p=0.042). In addition, RT significantly increased the expression of sPD-L1 (p = 0.000), which negatively associated with content of serum CD8+ T cells (R = -0.24, p = 0.033). Moreover, no significant associations were found between clinicopathological features and sPD-1. In cohort 2, we confirmed the phenomenon that RT could increase the expression of PD-L1 in tumor tissues (p = 0.001) and the expression level of PD-L1 in tumor tissues was related to decreased cytotoxic T-cell infiltration and a trend of poor prognosis. <h3>Conclusion</h3> High PD-L1 expression was associated with poor prognoses in HCC treated with RT. The increases in PD-L1 induced by RT indicated the combined treatment with RT and immune therapy may be promising strategy for HCC.

Higher serum sPD-L1 levels after radiotherapy indicate poor outcome in hepatocellular carcinoma patients

BackgroundOur preclinical research reveals that radiotherapy (RT) promoted PD-L1 upregulation in tumor tissues and that higher PD-L1 after RT worsened the prognosis through immunosuppression. We sought to validate our experimental results in clinical cohorts and promote clinical application. Patients and methodsIn cohort 1, formalin-fixed paraffin-embedded samples were obtained from 46 HCC patients, 23 of whom received preoperative RT and the other 23 received direct surgery. A prospectively collected database contained 122 HCC patients treated with liver RT were enrolled in cohort 2. Blood samples were taken a day before and two weeks after RT. Patients in cohort 2 were further divided into two groups, exploration (73 patients) and validation (49 patients) groups. ResultsIn cohort 1, RT increased the expression of PD-L1 in tumor tissues (p = 0.001), and PD-L1 levels were associated with decreased cytotoxic T-cell infiltration and a trend toward poor prognosis (p = 0.14). Moreover, PD-L1 expression in tumor tissue positively correlated with soluble (s) PD-L1 in serum (R = 0.421, p = 0.046). Then, in cohort 2, we revealed RT increased sPD-L1 in serum (p < 0.001), which was associated with the number of circulating CD8+ T cells (R = -0.24, p = 0.036), indicating poor survival. Furthermore, patients with higher rate of sPD-L1 increase after RT have better treatment response (p < 0.001), PFS (p = 0.032) and OS (p = 0.045). ConclusionHigher post-RT serum sPD-L1, which may potentiate immune suppression effects, indicates a poor prognosis for HCC patients treated with RT.

Soluble PD-L1 in blood correlates positively with neutrophil and negatively with lymphocyte mRNA markers and implies adverse sepsis outcome

Sepsis causes a myriad of immunological reactions that result in life-threatening alterations in the human body. Immunosuppression in sepsis is partly attributed to the programmed death receptor (PD-1) and its associated ligand (PD-L1) via the regulation of lymphocytes and neutrophils. Although the soluble forms of these proteins (i.e., sPD-1 and sPD-L1, respectively) are recognized as possible sepsis biomarkers, their functional implications are yet to be elucidated. Our research assessed the correlation between sPD-1 and sPD-L1 and blood mRNA markers and sepsis outcome. Blood samples of septic patients of urogenital origin versus control patients (both groups: n = 18) were analyzed. Blood serum sPD-1 and sPD-L1 levels were determined using the enzyme-linked immunosorbent assay (ELISA). The whole blood mRNA concentrations of PD-1, PD-L1, neutrophil markers (CEACAM8 and MPO), and T-lymphocyte markers (TCRβ, CD4 and CD8) were determined via reverse transcriptase quantitative PCR (RT-qPCR). sPD-L1 levels were significantly increased in septic patients when compared to the controls, whereas sPD-1 levels were unaltered. Patients with high sPD-L1 levels, as dichotomized to the median, had a significantly shorter survival rate than those with low sPD-L1 levels. The sensitivity/specificity characteristics of sPD-L1 proved significant for sepsis detection. Furthermore, sPD-L1 correlated with the mRNA concentrations of PD-L1, CEACAM, and MPO, as well as major inflammatory markers (C-reactive protein and procalcitonin). However, sPD-L1 negatively correlated with TCRβ, CD4, and CD8 mRNAs. sPD-L1 was found to be significantly increased in septic patients. Notably, sPD-L1 correlated with PD-L1 mRNA and neutrophil markers and was indicative of adverse outcomes.

The Relationship Between Soluble PD-L1 and Viral Infection, ACR, and CLAD

<h3>Purpose</h3> Respiratory viral infection (RVI) after lung transplant (LTx) is a risk factor for chronic lung allograft dysfunction (CLAD), but the mechanisms underlying this association are poorly understood. PD-L1 plays a key role in the normal host immune response to viruses. We hypothesized soluble PD-L1 (sPD-L1) levels are higher in subjects with RVI vs. acute cellular rejection (ACR), and that these levels may risk stratify patients for the development of CLAD. <h3>Methods</h3> We conducted a retrospective cohort study of LTx recipients with serum collected at the time of suspicion for RVI or ACR. At the time of sampling, 40 subjects had RVI and 27 subjects had ACR without RVI. We compared sPD-L1 levels between groups and tested for associations with the development of CLAD by 1-year post-infection. We are validating our findings in a prospective cohort that is enrolling subjects undergoing for-cause bronchoscopy with RVI (n = 7), ACR without RVI (n = 21), and without RVI or ACR (n = 22) with paired plasma and bronchoalveolar lavage fluid (BALF). <h3>Results</h3> In the retrospective cohort, subjects with RVI had 1.73-fold (95% CI 1.4 - 2.1) higher levels of serum sPD-L1 levels vs. subjects with ACR (without RVI) (p < 0.01). Doubling of serum sPD-L1 levels in subjects with RVI was associated with a higher risk for CLAD by 1-year post-infection (RR 4.96, 95% CI 1.64 - 15.0, p < 0.01, adjusting for age and sex). In contrast, there was no association between sPD-L1 levels at ACR (without RVI) and development of CLAD (RR 0.63, 95% CI 0.2 - 2.6, p = 0.50). In the prospective cohort, subjects with RVI again had significantly higher median plasma sPD-L1 levels (270 pg/ml) vs. subjects with ACR (without RVI) (173 pg/ml) (p < 0.01). Subjects without RVI or ACR had plasma values that were in between these two groups (median 222 pg/ml). BALF concentrations of sPD-L1 were not different between subjects in the 3 groups (beta: -0.1, p = 0.84) despite significant differences in the plasma (beta: -0.63, p < 0.01). <h3>Conclusion</h3> Higher levels of sPD-L1 at the time of RVI were associated with a higher risk for CLAD by 1-year post-infection. We are validating these findings prospectively, where peripheral blood (but not BALF) levels of sPD-L1 are significantly higher in subjects with RVI vs. ACR (without RVI). Our findings suggest PD-L1 may play divergent roles in the development of CLAD in two populations with key risk factors (RVI and ACR) for poor outcomes following LTx.

Circulating Levels of PD-L1, TIM-3 and MMP-7 Are Promising Biomarkers to Differentiate COVID-19 Patients That Require Invasive Mechanical Ventilation.

Background: COVID-19 is an infectious disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Many COVID-19 patients require invasive mechanical ventilation (IMV) while others, even with acute respiratory failure, do not (NIMV). Therefore, we aimed to evaluate serum levels of MMP-7 and molecules related to exhausted T-cells as potential biomarkers to differentiate between IMV and NIMV patients. Methods: 105 patients diagnosed with COVID-19 and confirmed by RT-PCR for SARS-CoV-2 were divided into two groups according to the requirement for IMV. Serum levels of sPD-L1, sPD-L2, sTIM-3, sGal-9 and sMMP-7 were quantified by ELISA and correlated with clinical data. Twelve patients were followed up after eight months to compare the levels of the biomarkers between acute disease and post-COVID-19. Results: IMV patients experienced a lower PaO2/FiO2 (p < 0.0001) and a longer hospital stay (p < 0.0001), and exhibited higher levels of sPD-L1 (p < 0.05), sTIM-3 (p < 0.01) and sMMP-7 (p < 0.0001) when compared with NIMV patients. According to a ROC analysis, sMMP-7 had the highest sensitivity (78%) and specificity (76%) with a cut point of 4.5 ng/mL, followed by sTIM-3 and sPD-L1. Eight months post-COVID-19, IMV patients displayed a significant decrease in the initially high levels of sPD-L1, sTIM-3 and sGal-9, while sPD-L2 was increased, and sMMP-7 was unchanged. Conclusion: Circulating levels of sPD-L1, sTIM-3 and sMMP-7 are potential biomarkers of disease severity to distinguish patients requiring IMV. MMP-7 could also be a marker for the persistence of lung lesions post-COVID-19.

Soluble forms of PD-1/PD-L immune checkpoint receptor and ligand in blood serum of breast cancer patients: association with clinical pathologic factors and molecular type of the tumor.

Results of enzyme-linked immunosorbent assay of the soluble forms of PD-1/PD-L immune checkpoint receptor and ligand (sPD-1 and sPD-L1) in pretreatment blood serum of 88 breast cancer patients at various disease stages aged 30-83 years are presented. The control group included 55 practically healthy women aged 19-82 years. Serum sPD-1 and sPD-L1 levels in breast cancer patients highly significantly (p<0.0001) differ from control and these changes are opposite: soluble receptor level is more than 6-fold decreased, while soluble ligand concentration - 5.5 fold increased. Both markers separately, as well as their ratio demonstrate very high sensitivity (94-100%) and specificity (95-100%) in relation to healthy control. No statistically significant associations of sPD-1 and sPD-L1 levels with clinical stage, individual TNM system criteria, tumor histological structure, grade, receptor status, and molecular type were established. In particular, no significant peculiarities of the markers' levels in triple negative breast cancer successfully treated with anti-PD-1/PD-L1 preparations were revealed. Long-term follow-up and dynamic studies of sPD-1 and sPD-L1serum levels in the course of treatment are required for evaluation of their independent from clinical and morphological factors prognostic significance and the possibility of application as low invasive tests for prediction and monitoring of corresponding targeted therapy efficiency.

Soluble PD-L1 as an early marker of progressive disease on nivolumab

BackgroundSoluble PD-L1 (sPD-L1) has been associated with worse prognosis in numerous solid tumors. We determined sPD-L1 levels before and during nivolumab treatment in two prospective clinical trials of metastatic clear...

Soluble PD-L1 Concentration Is Proportional to the Expression of PD-L1 in Tissue and Is Associated with a Poor Prognosis in Esophageal Squamous Cell Carcinoma

Introduction: We determined the soluble programmed cell death-1 ligand-1 (sPD-L1) concentration in patients with esophageal squamous cell carcinoma (ESCC), and confirmed the PD-L1 expression in resected specimens. Methods: Blood samples were collected from 73 patients with histologically proven ESCC. The serum levels of sPD-L1 were measured using an enzyme-linked immunosorbent assay. The correlations between the sPD-L1 concentration and the expression of PD-L1 in tumor specimens and tumor depth, lymph node metastasis, disease stage, and various laboratory data were assessed. Results: sPD-L1 levels in patients with high PD-L1 expression levels in tumor tissue were significantly higher than in patients with low PD-L1 expression levels (p = 0.042). The OS of the sPD-L1-high group was significantly worse than that of the low group (p = 0.028). Similarly, patients in whom a tissue specimen was PD-L1-positive group showed significantly poorer OS. Conclusion: The sPD-L1 concentration was correlated with the PD-L1 expression in tissues. Patients with PD-L1-positive tissue specimens showed significantly higher sPD-L1 levels in comparison to PD-L1-negative cases. Furthermore, patients with high sPD-L1 expression levels had a significantly worse prognosis than those with low sPD-L1 expression levels, and patients with a PD-L1-positive tissue specimen had a significantly worse prognosis than patients in whom the tissue specimen showed a low PD-L1 expression level.

Soluble PD-L1 in Serum and Urine in Urinary Bladder Cancer Patients.

Simple SummaryNon-invasive diagnostic and prognostic biomarkers for urinary bladder cancer (BC) are eagerly awaited, since these could improve patient’s quality of life and reduce resources and costs for the health care system. The PD-1/PD-L1 axis is an important immune escape mechanism for tumors, and both high tissue expression and soluble levels of PD-L1 have been shown to be associated with worse prognosis for patients with various tumor. The knowledge about soluble PD-L1 in body fluids such as serum and urine in patients with BC is sparse, and more studies are needed to investigate its role as a biomarker for the disease. In the present study, we show that high serum PD-L1 levels are associated with aggressive disease and development of metastatic disease in BC patients.Soluble PD-L1 (sPD-L1) levels have been identified as a potential biomarker for various cancers, but its diagnostic and prognostic value in urinary bladder cancer (BC) remains to be fully elucidated. In this study, we investigated sPD-L1 levels in serum and urine samples from 132 patients with BC and compared them to 51 patients with hematuria (controls). The levels of sPD-L1 in serum and urine were determined using ELISA. Soluble PD-L1 could be detected in 99.5% of the serum samples and 34.4% of the urine samples. Patients diagnosed with BC had significantly higher urinary levels of sPD-L1, compared to controls, however no difference were found in serum sPD-L1 levels (p = 0.038 and p = 0.61, respectively). Significantly higher serum sPD-L1 levels were found in patients with muscle invasive disease and metastatic disease, compared to patients with non-muscle invasive BC and non-metastatic disease (p < 0.05). There was also a trend for higher urine sPD-L1 levels in patients with metastatic disease, compared to patients with non-metastatic disease (p = 0.05). The results from this study suggest that sPD-L1 in serum, but not in urine, could be a potential prognostic biomarker for patients with BC.

Abstract 10471: Prognostic Significance of Soluble Programed Cell Death Ligand-1 on Cardiovascular Outcomes in Patients with Atherosclerotic Cardiovascular Disease

Background: Programmed Death-1(PD-1) and its ligand, PD-L1 regulate T cell proliferation and secretion of cytokines, leading to immunotolerance. A previous experimental study reported increased expression of PD-L1 in myocardium. Hence, PD-L1 could be associated with atherosclerotic cardiovascular disease (ASCVD). We hypothesized that serum soluble PD-L1 (sPD-L1) could be associated with cardiovascular events. We prospectively investigated the association between the serum levels of sPD-L1 and cardiovascular outcomes in patients with ASCVD. Methods: We prospectively measured sPD-L1 in patients with ASCVD admitted to Kumamoto University Hospital using a commercially available enzyme-linked immunosorbent assay kit and observed the occurrence of cardiovascular events between December 2017 and June 2019. The primary outcome was a composite of death from any cause, death from cardiovascular causes, nonfatal myocardial infarction, unstable angina pectoris, stroke, and heart failure hospitalization. We excluded patients complicated with cancer, hemodialysis, active collagen diseases, and inflammatory diseases. Results: Finally, 446 patients with ASCVD were enrolled. Median follow-up period was 322 days. A total of 153 events were recorded. Kaplan-Meier curve revealed that the higher sPD-L1 group (sPD-L1 ≧155pg/dL, median) showed significantly higher rate of cardiovascular events than the lower sPD-L1 group (19.2% vs. 28.1%, log-rank test: P =0.044). Univariate Cox proportional hazards analysis showed that creatinine, low density-lipoprotein cholesterol, B-type natriuretic peptide (BNP), and higher sPD-L1 (≧155pg/dL) were significantly associated with cardiovascular events. Multivariable Cox proportional hazards analysis by significant factors from univariate analysis identified that higher sPD-L1 [hazard ratio (HR): 1.699, 95% confidence interval (CI): 1.023-2.823, P =.041) and BNP (HR: 1.001, 95% CI: 1.000-1.001, P =0.036) were significantly and independently associated with cardiovascular events. Conclusions: The higher levels of sPD-L1 were significantly associated with near future cardiovascular events in patients with ASCVD, suggesting sPD-L1 could be a novel prognostic predictor in patients with ASCVD.

Serum-soluble PD-L1 may be a potential diagnostic biomarker in sepsis.

To investigate whether serum-soluble PD-L1 (sPD-L1) is a potential biomarker for identifying sepsis. This study enrolled 64 septic patients, 29 patients with acute appendicitis, 33 patients with acute pancreatitis and 30 healthy volunteers. Sepsis was defined according to the Sepsis 3.0 criteria.[1] The associated clinical parameters were recorded, blood samples were collected on the first day of diagnosis, and serum sPD-L1 levels were measured using enzyme-linked immunosorbent assays. Compared with the control group, a significant increase in sPD-L1 levels was observed in patients with sepsis (n=64). Increased sPD-L1 expression correlated strongly with increased clinical inflammatory values (CRP, PCT and WBC) and decreased immunological functional parameters (CD3+ , CD4+ and CD8+ cell counts). The area under the ROC curve (AUC) for sPD-L1 in combination with the sequential organ failure assessment (SOFA) score was superior to the AUC for either sPD-L1 or SOFA score in regard to the diagnosis of sepsis. sPD-L1 may represent a valuable biomarker for the diagnosis of sepsis.

Epstein-Barr Virus LMP1 Induces Soluble PD-L1 in Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy. The principal oncogene of EBV, latent membrane protein 1 (LMP1), induces the expression of programmed death-ligand 1 (PD-L1), which is an immunosuppressive transmembrane protein and a promising therapeutic target for various malignancies. Recent studies have revealed an association between the level of soluble PD-L1 (sPD-L1) and disease progression. However, the role of sPD-L1 in NPC or its relevance to LMP1 has not been elucidated. This study aimed to examine whether LMP1 induces sPD-L1 in vitro and analyze the clinical relevance of LMP1, PD-L1, and sPD-L1 in NPC patients. Analysis of nasopharyngeal cell lines revealed that LMP1 induces both cellular PD-L1 and sPD-L1. Analysis of biopsy specimens from 32 NPC patients revealed that LMP1 expression was significantly correlated with PD-L1 expression. Finally, the serum sPD-L1 level in NPC patients was higher than that in the controls. Moreover, the sPD-L1 level in the advanced stage was higher than that in the early stage. However, LMP1 expression, PD-L1 expression, and sPD-L1 levels were not associated with prognosis. These results suggest that LMP1 induces both sPD-L1 and PD-L1, which are associated with NPC progression.