Soluble Programmed Cell Death Ligand Research Articles

Mitochondria-Targeting Polymer Micelle of Dichloroacetate Induced Pyroptosis to Enhance Osteosarcoma Immunotherapy.

Pyroptosis has been reported to improve the immunosuppressive tumor microenvironment and may be a strategy to enhance osteosarcoma treatment. The extent to which modulation of mitochondria could induce tumor pyroptosis to enhance immunotherapy has not been characterized. We synthesized a mitochondria-targeting polymer micelle (OPDEA-PDCA), in which poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA) was used to target mitochondria and the conjugated dichloroacetate (DCA) was used to inhibit pyruvate dehydrogenase kinase 1 (PDHK1). This conjugate induced pyroptosis through initiation of mitochondrial oxidative stress. We found that OPDEA-PDCA targeted mitochondria and induced mitochondrial oxidative stress through the inhibition of PDHK1, resulting in immunogenic pyroptosis in osteosarcoma cell lines. Moreover, we showed that OPDEA-PDCA could induce secretion of soluble programmed cell death-ligand 1 (PD-L1) molecule. Therefore, combined therapy with OPDEA-PDCA and an anti-PD-L1 monoclonal antibody significantly suppressed proliferation of osteosarcoma with prolonged T cell activation. This study provided a strategy to initiate pyroptosis through targeted modulation of mitochondria, which may promote enhanced antitumor efficacy in combination with immunotherapy.

SO-8 Soluble programmed cell death ligand 1 associated with clinical outcome in gastric cancer patients treated with nivolumab: Blood based biomarker analysis of DELIVER trial (JACCRO-GC08AR)

The potential predictive value of soluble checkpoint molecules for immune checkpoint inhibitor has been shown in several malignancies including non-small cell lung cancer and renal cell carcinoma, but not in gastric cancer. We thus assessed the association of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1) and soluble Cytotoxic T-Lymphocyte-Associated protein 4 (sCTLA-4) with efficacy measures including survival in advanced gastric cancer patients treated with nivolumab monotherapy using blood samples collected from a prospective observational and translational study (DELIVER [JACCRO-GC08] trial).

Krebs von den Lungen-6 (KL-6), soluble programmed cell death-1 (sPD-1) and its ligand-1(sPDL-1) in systemic sclerosis patients: Relation to disease parameters

Aim of the workThis study aimed to assess the levels of Krebs von den Lungen-6 (KL-6), soluble programmed cell death-1 (sPD-1) and soluble programmed cell death ligand-1(sPDL-1) in systemic sclerosis (SSc) patients, and to evaluate their relation with disease parameters. Patients and methodsForty-six SSc patients (31 limited, 15 diffuse) and 43 matched controls were included. Serum levels of KL-6, sPD-1, and sPDL-1 were assessed by enzyme-linked immune-sorbent assay (ELISA). ResultsPatients mean age was 40.2 ± 12.2 years, disease duration 8.04 ± 6.02 years and females: male was 10.5:1. Levels of KL-6, sPD-1, and sPDL-1 were significantly higher in SSc patients compared to the controls 22.4(14.1–637.6) vs. 14.8(8.9–182.3) (p < 0.001), 3.1(1.8–64.2) vs. 1.2(0.68–14.4) (p < 0.001), and 2.8(1.5–84.4) vs. 1.4(0.92–36.4) (p < 0.001) respectively. KL-6 and sPD-1 levels were significantly lower in diffuse SSc subtype than the limited subtype 20.7(14.1–637.6) vs. 24.5(16.2–328.8) (p = 0.01), and 2.5(1.8–64.2) vs. 3.2(2.1–63.4) (p = 0.03) respectively. KL-6 was significantly decreased in SSc patients who developed pulmonary hypertension compared to those without 20.9(14.1–36.3) vs. 27.5(16.5–637.6) (p = 0.02), and in those who received cyclophosphamide 21(14.1–310.9 vs. 31.6(16.2–637.6) (p = 0.019). The three markers were significantly correlated. KL-6 levels with sPD-1 (r = 0.79, p < 0.001) and sPDL-1 (r = 0.79, p < 0.001) and between sPD-1 and sPDL-1 (r = 0.82, p < 0.001) respectively. Both sPD-1 and sPDL-1 significantly correlated with age (r = 0.29, p = 0.048 and r = 0.34, p = 0.021 respectively). ConclusionsKL-6, sPD-1, and sPDL-1 may be considered as potential biomarkers in the diagnosis and assessment of SSc patients. Significantly lower levels of KL-6 were detected in diffuse SSc patients, those with pulmonary hypertension, and patients who received cyclophosphamide.

The influence of transarterial chemoembolization on serum levels of soluble programed cell death ligand-1 in advanced hepatocellular carcinoma patients.

To investigate the implications of soluble programmed cell death-ligand 1 (sPD-L1) in hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE) and to evaluate the potential value of sPD-L1 to guide selection of the optimal time to begin combination therapy with TACE and immune checkpoint inhibitors (ICIs). Thirty-one HCC patients suitable for TACE and 55 healthy volunteers were enrolled in this study. Three milliliters of peripheral venous blood of patients were collected on 1 day before TACE and 3, 7, and 30 days after TACE respectively for assay of sPD-L1 using enzyme-linked immunosorbent assay. The associations of the sPD-L1 level with the clinical features, outcomes, and the fluctuation of sPD-L1 during the treatment were analyzed. The initial sPD-L1 level of patients was significantly higher than that of the control group. And it was significantly associated with BCLC stage, portal venous invasion, tumor size, and number of foci. The sPD-L1 levels of 3 and 7 days after TACE were both significantly higher than the initial level. And that of 30 days after TACE was lower than the initial level, but the difference was not statistically significant. There was no significant difference of sPD-L1 level after embolization with embolic beads of different size. The level of sPD-L1 of CR patients was lower than that of PR, SD patients, but the differences were not significant. The level of sPD-L1 was associated with tumor aggressiveness and outcomes, suggesting its role as a possible predictive biomarker. The increases in sPD-L1 after TACE suggests that combined treatment with TACE and ICIs may be a promising therapeutic strategy in HCC. One week after TACE might be a suitable time to begin the administration of immunotherapy.

Oxidative stress and inflammation parameters-novel biomarkers for idiopathic pulmonary fibrosis.

The pathophysiological mechanisms of idiopathic pulmonary fibrosis (IPF) are not well elucidated. It is assumed that oxidative stress and inflammation are the key underlying culprits for its onset and progression. To gain deeper insight into these processes, we have evaluated several oxidative stress parameters, inflammation markers [i.e., high sensitivity C-reactive protein (hsCRP), serum amyloid A1 (SAA1)], soluble programmed cell death-ligand 1 (sPD-L1), and 25-hydroxyvitamin D [25(OH)D] in IPF patients. Biochemistry analyses were done in 30 consecutive IPF patients and 30 age and gender-matched healthy control group (CG). IPF patients had significantly higher advanced oxidation protein products (p<0.001), pro-oxidant-antioxidant balance (p=0.010), total oxidative status (p<0.001), and ischemia modified albumin (p<0.001) compared to CG. Lower total antioxidant status and total sulfhydryl groups (tSGH) and significantly higher sPD-L1, hsCRP (p<0.001 for all), SAA1 proteins (p=0.014) and [25(OH)D] severe deficiency [11.0 (9.6-15.1) nmol/L] in IPF patients compared to CG were observed. Paraoxonase 1 activity and hsCRP level were lower, while tSHG and sPD-L1 were higher in IPF patients with more severe disease (i.e., II+III stage compared to I stage, p<0.05 for all). IPF patients are in a state of profound oxidative stress compared to healthy people. The inflammatory component of the disease was confirmed by higher hsCRP and SAA1, but lower [25(OH)D] in IPF than in healthy people. Also, higher levels of sPD-L1 in patients with IPF compared to healthy individuals suggest that sPD-L1 may have a significant role in immune response in IPF.

Biomarkers for Locally Advanced Hepatocellular Carcinoma Patients Treated with Liver-Directed Combined Radiotherapy

Introduction: In the era of biomarker-driven cancer therapy, robust biomarkers for hepatocellular carcinoma (HCC) have not been well-defined. In this hypothesis-generating study, we investigated biomarkers that can be incorporated to predict treatment outcomes in patients with locally advanced HCC who are administered liver-directed combined radiotherapy (LDCRT). Methods: Ninety-nine patients with HCC who were treated with conventional fractionation LDCRT between July 2016 and October 2018 were enrolled in this prospective single-arm study. Clinical outcomes and possible serum biomarkers, including soluble programmed cell death ligand-1 (sPD-L1), interleukin (IL)-10, IL-6, cell-free DNA (cfDNA), inter-alpha inhibitor H4, and interferon-gamma, were analyzed. The primary endpoint was disease progression, and additional endpoints were local failure-free rate, intrahepatic failure-free rate, and lung metastasis-free rate. Results: The median follow-up period was 18.7 months. The 1-year progression-free rate was 38.2%. Increasing baseline sPD-L1 per pg/mL, previous treatment history, protein induced by vitamin K absence-II >1,629 mAU/mL, and multiple tumors were the adverse factors for progression based on multivariate analysis. Survival tree analysis revealed three prognostic groups for progression, in which patients with multiple lesions and baseline sPD-L1 ≥41.07 pg/mL showed the worst outcomes. For dynamic changes in biomarker levels, sPD-L1 fold change and cfDNA fold-change values were unfavorable factors for progression. Conclusion: Baseline sPD-L1, sPD-L1 fold change, and cfDNA fold-change values showed the highest potential as biomarkers for predicting post-treatment progression after LDCRT in HCC patients. By incorporating clinical factors, these biomarkers may be useful for devising a biomarker-driven treatment paradigm in locally advanced HCC.

Prognostic value of soluble programmed cell death-1 (sPD-1) and soluble programmed cell death ligand-1 (sPD-L1) for hepatocellular carcinoma: a systematic review and meta-analysis.

Preliminary studies have suggested that soluble programmed death-1 (sPD-1) and soluble programmed cell death ligand-1 (sPD-L1) have prognostic implications in many malignant tumors. However, the correlation between sPD-1/sPD-L1 level and prognosis of hepatocellular carcinoma (HCC) is still unclear. We searched several electronic databases from database inception to October 7, 2021. Meta-analyses were performed separately for overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), time to progression (TTP), and tumor-free survival (TFS). Random effects were introduced to this meta-analysis. The correlation between sPD-1/sPD-L1 level and prognosis was evaluated using hazard ratios (HRs) with 95% confidence intervals (95%CIs). A total of 11 studies (1291 patients) were incorporated into this meta-analysis, including seven on sPD-L1, two on sPD-1, and two about both factors. The pooled results showed that high sPD-L1 level was associated with worse OS (HR = 2.46, 95%CI 1.74-3.49, P < 0.001; I2 = 31.4, P = 0.177) and poorer DFS/RFS/TTP/TFS of patients with HCC (HR = 2.22, 95%CI 1.47-3.35, P < 0.001; I2 = 66.1, P = 0.011), irrespective of method of detection, study type, treatment, cut-off value and follow-up time. In contrast, the level of sPD-1 was not correlated to the OS (HR = 1.19, 95%CI 0.55-2.56, P = 0.657) and DFS/TFS of patients with HCC (HR = 0.94, 95%CI 0.36-2.49, P = 0.906). sPD-L1 rather than sPD-1 could be a good predictor for recurrence and survival after treatment for HCC. More high-quality prospective studies are warranted to assess the prognostic value of sPD-1 or sPD-L1 for HCC.

Stem cells from exfoliated deciduous teeth transplantation ameliorates Sjögren's syndrome by secreting soluble PD-L1

Mesenchymal stem cell transplantation (MSCT) regulates immune cells, and is a promising therapeutic approach for treating autoimmune diseases. Stem cells from human exfoliated deciduous teeth (SHED) are a unique postnatal stem cell population from the cranial neural crest with high self-renewal, multipotent differentiation, and superior immunomodulatory properties. However, the mechanisms by which SHED can treat autoimmune diseases remain unclear. Sjögren's syndrome (SS) is an autoimmune disease histologically characterized by high lymphocytic infiltration in the salivary and lacrimal glands that results in dryness symptoms. This study explores the potential of systemic transplantation of SHED to ameliorate SS-induced dryness symptoms in mice. Overall, SHED could rescue the balance of regulatory T cell (Treg)/T helper cell 17 (Th17) in the recipient SS mice. Mechanistically, SHED promoted Treg conversion and inhibited Th17 function via paracrine effects, which were related to the secretion of soluble programmed cell death ligand 1 (sPD-L1). Moreover, it directly induced Th17 apoptosis via cell-cell contact, leading to the up-regulation of Treg and down-regulation of Th17 cells. In summary, SHED-mediated rescue of Treg/Th17 balance via the sPD-L1/PD-1 pathway ameliorates the gland inflammation and dryness symptoms in SS mice. These findings suggest that SHED are a promising stem cell source for the treatment of autoimmune diseases in the clinical setting.

Prognostic prospect of soluble programmed cell death ligand-1 in cancer management.

Aggressive tissue biopsy is commonly unavoidable in the management of most suspected tumor cases to conclusively verify the presence of cancerous cells through histological assessment. The extracted tissue is also immunostained for detection of antigens (tissue tumor markers) of potential prognostic or therapeutic importance to assist in treatment decision. Although liquid biopsies can be a powerful tool for monitoring treatment response, they are still excluded from standard cancer diagnostics, and their utility is still being debated in the scientific community. With a myriad of soluble tissue tumor markers now being discovered, liquid biopsies could completely change the current paradigms of cancer management. Recently, soluble programmed cell death ligand-1 (sPD-L1), which is found in the peripheral blood, i.e. serum and plasma, has shown potential as a pre-therapeutic predictive marker as well as a prognostic biomarker to monitor treatment efficacy. Thus, this review focuses on the emergence of sPD-L1 and promising technologies for its detection in order to support liquid biopsies for future cancer management.

The clinical implication of soluble PD-L1 (sPD-L1) in patients with breast cancer and its biological function in regulating the function of T lymphocyte

This work investigated the clinical prognostic implications and biological function of plasma soluble programmed cell death ligand 1 in breast cancer patients. Plasma sPD-L1 levels of recurrent/metastatic breast cancer patients were determined, and the association of sPD-L1 levels and metastatic progression-free survival and metastatic overall survival was assessed. The PD-L1 expression on breast cancer cells was analyzed by flow cytometry, and the level of sPD-L1 in the supernatant of breast cancer cells was determined by enzyme-linked immunosorbent assay. Furthermore, the effect of sPD-L1 on the proliferation and apoptosis of T lymphocytes was detected by WST-1 assay and flow cytometry. The plasma sPD-L1 levels in 208 patients with recurrent/metastatic breast cancer before receiving first-line rescue therapy were measured. The optimal cutoff value of plasma sPD-L1 for predicting disease progression was 8.774 ng/ml. Univariate and multivariate analyses identified high sPD-L1 level (≥ 8.774 ng/ml) and visceral metastasis were independent factors associated with poor prognosis. Relevance analysis showed that the plasma sPD-L1 level was weaklyassociated with some systemic inflammation markers, including white cell count (WBC), absolute monocytecount, and absolute neutrophil count. Furthermore, we found sPD-L1 could be found in supernatant of culture with breast cancer cell line expressing PD-L1 on the cell surface and inhibit T lymphocyte function, playing a negative regulatory role in cellular immunity. sPD-L1 was a good tumor predictive maker in breast cancer and it may play a potentially important role in immune tolerance.

The expression and clinical significance of serum soluble programmed cell death ligand-1 in adult patients with community-acquired pneumonia

To investigate the clinical significance of serum soluble programmed cell death ligand-1 (PD-L1) in adult patients with community-acquired pneumonia (CAP). A total of 44 CAP patients, 54 severe CAP patients and 30 healthy volunteers were recruited in this study. Serum soluble PD-L1 were detected. Univariate and multivariate regression analyses were used to assess the influence of multiple clinical variables on prognosis. Serum soluble PD-L1 level in severe CAP group was 98.20(57.94, 128.90) ng/L, which was significantly higher than that in the CAP group [59.32(33.55, 92.58) ng/L] and healthy controls [20.44(12.15, 36.20) ng/L] (all P<0.001). PD-L1 level was positively correlated with CRUB-65(r=0.481, P<0.001) and the pneumonia severity index (PSI) score (r=0.442, P<0.001). Univariate regression analysis showed that CURB-65 (HR=2.544, 95%CI 1.324-4.889, P=0.005), PSI score (HR=1.036, 95%CI 1.012-1.061, P=0.004), soluble PD-L1(HR=1.013, 95%CI 1.001-1.026, P=0.041) were risk factors of mortality during hospitalization. Multivariate regression analysis suggested that PSI score (HR=1.042, 95%CI 1.012-1.073, P=0.005), soluble PD-L1 (HR=1.011, 95%CI 1.002-1.071, P=0.020) were independent predictors for mortality risk in CAP patients. CAP patients with soluble PD-L1≥98.20 ng/L had a significantly lower survival rate than those with soluble PD-L1<98.20 ng/L (P=0.033). In conclusion, this study indicates that serum soluble PD-L1 level in CAP patients is correlated with the survival prognosis.

Immune checkpoint expression on peripheral cytotoxic lymphocytes in cervical cancer patients: moving beyond the PD-1/PD-L1 axis.

Immune checkpoint therapy to reverse natural killer (NK) and T cell exhaustion has emerged as a promising treatment in various cancers. While anti-programmed cell death 1 (PD-1) pembrolizumab has recently gained Food and Drug Administration (FDA) approval for use in recurrent or metastatic cervical cancer, other checkpoint molecules, such as T cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibition motif (ITIM) domains (TIGIT) and T cell immunoglobulin and mucin-domain containing-3 (Tim-3), have yet to be fully explored in this disease. We report expression of TIGIT, Tim-3 and PD-1 on subsets of peripheral blood NK (CD56dim/neg CD16bright/dim/neg and CD56bright CD16dim/neg ) and T cells. The percentages of these cells were increased in women with cervical cancer and pre-malignant lesions. PD-1+ NK and T cells were likely to co-express TIGIT and/or Tim-3. These cells, with an apparently 'exhausted' phenotype, were augmented in patients. A subset of cells were also natural killer group 2 member D (NKG2D)- and DNAX accessory molecule 1 (DNAM-1)-positive. PD-1int and PD-1high T cells were notably increased in cervical cancer. Soluble programmed cell death ligand 1 (PD-L1) was higher in cancer patient blood versus healthy donors and we observed a positive correlation between sPD-L1 and PD-1+ T cells in women with low-grade lesions. Within the cancer group, there were no significant correlations between sPD-L1 levels and cervical cancer stage. However, when comparing cancer versus healthy donors, we observed an inverse association between sPD-L1 and total T cells and a correlation between sPD-L1 and CD56dim NK cells. Our results may show an overview of the immune response towards pre-cancerous lesions and cervical cancer, perhaps giving an early clue as to whom to administer blocking therapies. The increase of multiple checkpoint markers may aid in identifying patients uniquely responsive to combined antibody therapies.

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.

The Change of Soluble Programmed Cell Death-Ligand 1 in Glioma Patients Receiving Radiotherapy and Its Impact on Clinical Outcomes.

BackgroundThe programmed cell death ligand 1 (PD-L1) plays a key role in glioma development. However, due to the specificity of glioma’s anatomical position, the role of its expression as a tumor biomarker is limited. It has been proven that the levels of soluble programmed death-ligand 1 (sPD-L1) are associated with prognosis in many malignancies including glioma. However, the expression of sPD-L1 in glioma patients receiving radiotherapy (RT) remains unclear. The purpose of this study was to evaluate the concentration of sPD-L1 in the plasma of glioma patients before and after RT and to explore its relationship with clinical outcomes.MethodsBetween October 2017 and September 2018, glioma patients treated with RT (30 ± 10 Gy, 2 Gy/f) were enrolled, and blood samples were collected before and after RT. We quantified the sPD-L1 levels by enzyme-linked immunosorbent assay (ELISA). The isocitrate dehydrogenase-1 (IDH-1) mutational status and Ki-67 expression of tumors were evaluated by immunohistochemistry. Glioma murine model were used to address whether circulating sPD-L1 molecules are directly targeted by an anti-PD-L1 antibody. The associations between sPD-L1 and clinical features were assessed with Pearson’s or Spearman’s correlation analysis. The progression-free survival (PFS) and overall survival (OS) were determined by the Kaplan-Meier method.ResultsSixty glioma patients were included, with a median age of 52 years. The proportions of grade I, II, III, and IV gliomas were 6.7%, 23.3%, 28.4%, and 41.6%, respectively. The baseline sPD-L1 levels were significantly associated with tumor grade, IDH-1 mutation status and Ki-67 expression. Using 14.35 pg/ml as the cutoff, significantly worse PFS and OS were both observed in patients with higher baseline levels of sPD-L1 (P = 0.027 and 0.008, respectively). RT significantly increased the mean level of sPD-L1 (P < 0.001). Further analysis showed that the level of sPD-L1 in IDH-1 mutation patients was higher than that in wild-type patients. Furthermore, an analysis of glioma murine model indicated that anti-PD-L1 antibody combine with RT can be a potentially powerful cancer therapy.ConclusionThis study reported that sPD-L1 might be a potential biomarker to predict the outcome in glioma patients receiving RT. The elevated level of sPD-L1 after RT suggested that the strategy of a combination of immune checkpoint inhibitors and RT might be promising for glioma patients, especially for those with IDH-1 mutations.

Association between serum level soluble programmed cell death ligand 1 and prognosis in patients with non-small cell lung cancer treated with anti-PD-1 antibody.

BackgroundProgrammed cell death ligand 1 (PD‐L1) is known to have soluble forms aside from its membrane‐bound forms. The aim of this study was to evaluate the predictive and prognostic values of serum soluble PD‐L1 (sPD‐L1) in patients with non‐small cell lung cancer (NSCLC) who were treated with anti‐PD‐1 antibody.MethodsA total of 233 patients were enrolled in this study. We assessed the level of serum sPD‐L1 before anti‐PD‐1 antibody treatment (pembrolizumab or nivolumab) and evaluated the correlation with PD‐L1 expression on tumor cells, the response to anti‐PD‐1 antibody treatment, and patient outcome.ResultsThe median serum sPD‐L1 concentration was 67.7 (range, 25 to 223) pg/mL. A weak correlation between serum sPD‐L1 and tumor PD‐L1 expression was observed. The disease control rate in the high sPD‐L1 group (≥90 pg/mL) was significantly lower than that in the low sPD‐L1 group (<90 pg/mL) (37% vs. 57%, P = 0.0158). The progression‐free survival (PFS) and overall survival (OS) in the high sPD‐L1 group were significantly shorter than those in the low sPD‐L1 group (median PFS, 57 days vs. 177 days, P = 0.011; median OS, 182 days vs. not reached, P < 0.001). The high level of serum sPD‐L1 was independently associated with a shorter PFS (hazard ratio [HR], 1.910; P = 0.061) and OS (HR, 2.073; P = 0.034) in multivariate analysis.ConclusionsThe serum sPD‐L1 level, which was only weakly correlated with the tumor PD‐L1 expression level, was an independent predictive and prognostic biomarker for NSCLC patients receiving anti‐PD‐1 antibody.Key pointsSignificant findings of the studyThe disease control rate in the high sPD‐L1 group was significantly lower than that in the low sPD‐L1 group. The progression‐free survival (PFS) and overall survival (OS) in the high sPD‐L1 group were significantly shorter than those in the low sPD‐L1 group. The high level of serum sPD‐L1 was independently associated with a shorter PFS and OS in multivariate analysis.What this study addsThis study demonstrated that serum sPD‐L1 level was an independent predictive and prognostic biomarker for NSCLC patients receiving anti‐PD‐1 antibody.

The Change of Soluble Programmed Cell Death Ligand-1 (sPD-L1) in Patients with Glioma during Radiotherapy and Impact on Clinical Outcome

It has been proven that the levels of soluble programmed death-ligand 1 (sPD-L1) are associated with prognosis in extracranial malignancies. Nevertheless, due to the blood-brain barrier (BBB) the expression of sPD-L1 in patients with glioma is still unknown. The purpose of this study is to evaluate plasma concentrations of sPD-L1 before and after radiotherapy (RT) for patients with glioma, and investigate its relationships with clinical outcome. Between October 2017 and September 2018, glioma patients treated with RT were enrolled. Blood samples were collected before and after RT (30 ± 10 Gy, 2 Gy/f). We quantified the sPD-L1 levels using enzyme-linked immunosorbent assay (ELISA) kits. The isocitrate dehydrogenase-1 (IDH-1) promoter status and the expression of Ki-67 were also evaluated by immunohistochemistry (IHC). The associations between sPD-L1 level and the clinical features were assessed with Pearson or Spearman correlation. The progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier method. Sixty glioma patients were included, with the median age 52-year-old (range, 18 – 75 years). The proportion of grade I, II, III, IV were 6.7%, 25.0%, 26.7% and 41.6%, respectively. The sPD-L1 levels before RT were significantly associated with tumor grade (r = 0.495, P < 0.001), IDH-1 promoter status (r = 0.379, P = 0.016) and Ki-67 expression rate (r = 0.434, P = 0.003). Using 14.35 pg/mL as the cutoff, statistically significant worse PFS and OS were both noted in patients with higher sPD-L1 level before RT than those with lower ones (20.4 vs. 26.7 months, 23.1 vs. 28.7 months, P = 0.027, 0.008, respectively). Comparing with that before RT, the mean level of sPD-L1 significantly increased after RT (41.14 ± 52.41 vs. 52.49 ± 61.84 pg/ml, P = 0.011). sPD-L1 was increased in 31 patients, in contrast, that was reduced in 20 patients. Further analysis showed that the patients with decreased sPD-L1 had significantly worse OS (20.8% vs 29.5%, P = 0.040) than increased ones. The increased level of sPD-L1 in IDH-1 mutation patients was higher than that in wide-type ones. To the best of our known, this is the first study reported that PD-L1 can be assayed in peripheral blood of glioma patients. The reason might be that BBB is destroyed. sPD-L1 might be a potential biomarker to predict the outcome in glioma. The elevated level of sPD-L1 after RT suggests that the strategy of combination with immune checkpoint inhibitors and RT is promising for glioma, especially for patients with IDH-1 mutation.

Soluble PD-L1 as a Predictor of the Response to EGFR-TKIs in Non-small Cell Lung Cancer Patients With EGFR Mutations.

Programmed cell death ligand 1 (PD-L1) expressed on tumor tissues is a vital molecule for immune suppression and its impact on the response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has been reported. The significance of soluble PD-L1 (sPD-L1) for lung cancer patients remains unknown. This study investigated whether sPD-L1 could predict the response of EGFR-mutated non-small cell lung cancer (NSCLC) to EGFR-targeted therapy. We retrospectively evaluated patients who received first-line treatment with EGFR-TKIs for advanced NSCLC with EGFR mutations. Pre-treatment plasma concentrations of PD-L1 and on-treatment (1 month after treatment initiation) plasma concentrations of PD-L1 were measured using the R-plex Human PD-L1 assay. The association between the sPD-L1 level and the clinical outcome was analyzed. Among 66 patients who were eligible for the study, patients with high pre-treatment or on-treatment sPD-L1 levels had decreased objective response rate (ORR) compared with that of patients with low sPD-L1 levels (39.4 vs. 66.7%, p = 0.026 for pre-treatment sPD-L1 level, and 43.5 vs. 73.9%, p = 0.025 for on-treatment sPD-L1 level). A high baseline sPD-L1 level was associated with a shortened progression-free survival (PFS) rate (9.9 vs. 16.1 months, p = 0.005). Both univariate and multivariate analyses showed that a high baseline sPD-L1 level was an independent factor associated with the PFS (hazard ratio [HR] 2.56, p = 0.011). Our study revealed that the sPD-L1 level was strongly related to the outcome of EGFR-TKIs in NSCLC patients harboring EGFR mutations.

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.

Trophoblast-secreted soluble-PD-L1 modulates macrophage polarization and function

Decidual macrophages are in close contact with trophoblast cells during placenta development, and an appropriate crosstalk between these cellular compartments is crucial for the establishment and maintenance of a healthy pregnancy. During different phases of gestation, macrophages undergo dynamic changes to adjust to the different stages of fetal development. Trophoblast-secreted factors are considered the main modulators responsible for macrophage differentiation and function. However, the phenotype of these macrophages induced by trophoblast-secreted factors and the factors responsible for their polarization has not been elucidated. In this study, we characterized the phenotype and function of human trophoblast-induced macrophages. Using in vitro models, we found that human trophoblast-educated macrophages were CD14+ CD206+ CD86- and presented an unusual transcriptional profile in response to TLR4/LPS activation characterized by the expression of type I IFN-β expression. IFN-β further enhances the constitutive production of soluble programmed cell death ligand 1 (PD-L1) from trophoblast cells. PD-1 blockage inhibited trophoblast-induced macrophage differentiation. Soluble PD-L1 (sPD-L1) was detected in the blood of pregnant women and increased throughout the gestation. Collectively, our data suggest the existence of a regulatory circuit at the maternal fetal interface wherein IFN-β promotes sPD-L1 expression/secretion by trophoblast cells, which can then initiate a PD-L1/PD-1-mediated macrophage polarization toward an M2 phenotype, consequently decreasing inflammation. Macrophages then maintain the expression of sPD-L1 by the trophoblasts through IFN-βproduction induced through TLR4 ligation.

Dynamic monitoring of serum soluble programmed cell death ligand 1 as a response predictor to chemotherapy in metastatic or recurrent gastrointestinal cancer

BackgroundBiomarkers in serum may have important clinical implications for personalized medicine, including therapeutic guidance, and monitoring of recurrence. The role of programmed cell death ligand 1 (PD-L1) expression as a tumor biomarker remains controversial. In this study, we aimed at determining the changes of soluble PD-L1 (sPD-L1) during first-line chemotherapy and assessing the association with treatment response and progression-free survival (PFS) of patients with advanced gastrointestinal cancer.MethodsBlood samples from 115 gastrointestinal cancer patients who have not received any previous systemic chemotherapy for recurrent or metastatic disease were collected at the time of diagnosis and each response evaluation. Serum of sPD-L1 expression was tested by enzyme-linked immunosorbent assay (ELISA). The associations between the baseline level of serum sPD-L1 and clinical-pathological characteristics and prognosis were analyzed. we further dynamically monitored the level change of serum sPD-L1 during treatment and analyzed its relationship with clinical-pathological characteristics, chemotherapy response and prognosis.ResultsAmong 115 metastatic gastrointestinal patients, the median serum sPD-L1 level was 0.777 (range, <0.156–6.680) ng/mL. In most cases, changes in sPD-L1 level correlated with treatment response. Patients with values of serum sPD-L1 decreasing after chemotherapy had better tumor response and median PFS compared with patients with values increasing after chemotherapy (ORR, 88.3% vs. 54.0% P=0.000005 and PFS, not reached vs. 27 months, P=0.00026). D-values of sPD-L1 in patients with progressive disease (PD) were observed increasing from 0.406 to 1.097 ng/mL between pre- and post-chemotherapy, while in those with better tumor response D-values decreased from 1.153 to 0.791 ng/mL after chemotherapy compared with baseline. In the logistic regression analysis, the change of sPD-L1 levels in serum after chemotherapy were found to be a prognostic factor for treatment response and PFS in the multivariate analysis.ConclusionsThese results showed for the first time that sPD-L1 in serum samples of patients with advanced gastrointestinal cancer were changed after chemotherapy and increased serum sPD-L1 levels were poor prognostic factors for both tumor response and PFS of patients. Dynamic monitoring of serum sPDL1 after treatment may be served as a potential predictor to treatment response in gastrointestinal cancer patients.