PD-L1 Expression Is Associated With VEGFA and LADC Patients' Survival.
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SUBMITTER: Liu S
PROVIDER: S-EPMC6443993 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The aim of this study is to determine the significance of programmed death ligand 1 (PD-L1 or CD274) methylation in relation to PD-L1 expression and survival in melanoma. Despite the clinical importance of therapies targeting the PD-1/PD-L1 immune checkpoint in melanoma, factors regulating PD-L1 expression, including epigenetic mechanisms, are not completely understood. In this study, we examined PD-L1 promoter methylation in relation to PD-L1 expression and overall survival in melanoma patients. Our results suggest that DNA methylation regulates PD-L1 expression in melanoma, and we identify the key methylated CpG loci in the PD-L1 promoter, establish PD-L1 methylation as an independent survival prognostic factor, provide proof of concept for altering PD-L1 expression by hypomethylating agents, and uncover that PD-L1 methylation is associated with an interferon signaling transcriptional phenotype. Based on our findings, measuring and altering PD-L1 promoter DNA methylation may have potential prognostic and therapeutic applications in melanoma.
| S-EPMC6475614 | biostudies-literature
Project description:BackgroundThis study investigated the clinical relevance and prognostic impact of the overall expression of programmed cell death protein ligand-1 (PD-L1) and programmed cell death protein ligand-2 (PD-L2), in patients with Epstein-Barr virus-associated gastric cancer (EBVaGC).MethodsAfter reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, the expression status of PD-L1 and PD-L2 in 120 patients with EBVaGC identified by EBV-encoded RNA in situ hybridisation was retrospectively analysed using immunohistochemistry (IHC). For each IHC marker, positivity was separately in intraepithelial tumour cells (iTu-) and immune cells in the tumour stroma area (str-).ResultsAmong 116 eligible patients, 57 (49.1%) and 66 patients (56.9%) were determined as iTu-PD-L1-positive and str-PD-L1-positive, respectively, whereas 23 (21.6%) and 45 patients (38.8%) were determined as iTu-PD-L2 positive and str-PD-L2 positive, respectively. Intraepithelial tumour cell PD-L1 positivity was found to be significantly associated with lymph node (LN) metastasis (P=0.012) and a poor disease-free survival (DFS) (P=0.032), yet not overall survival (P=0.482). In a multivariate analysis, iTu-PD-L1 positivity was independently associated with a poor DFS (P=0.006, hazard ratio=12.085). In contrast, str-PD-L2-positivity was related to a lower T category (P=0.003), absence of LN metastasis (P=0.032) and perineural invasion (P=0.028). Intraepithelial tumour cell and str-PD-L2 positivity showed a trend towards an improved DFS, although not significant (P=0.060 and P=0.073, respectively).ConclusionsIntraepithelial tumour cells PD-L1 expression can be used to predict a poor outcome in patients with EBVaGC and can represent a rational approach for PD-1/PD-L pathway-targeted immunotherapy.
| S-EPMC5729479 | biostudies-literature
Project description:Background: Lung cancer treatment has become increasingly dependent upon invasive biopsies to profile tumors for personalized therapy. Recently, tumor expression of programmed death-ligand 1 (PD-L1) has gained interest as a potential predictor of response to immunotherapy. Circulating biomarkers present an opportunity for tumor profiling without the risks of invasive procedures. We characterized PD-L1 expression within populations of nucleated cells in the peripheral blood of lung cancer patients in hopes of expanding the role of liquid biopsy in this setting.Methods: Peripheral blood samples from a multi-institutional prospective study of patients with clinical diagnosis of lung cancer were subjected to cytomorphometric and immunohistochemical evaluation using single-cell, automated slide-based, digital pathology. PD-L1 expression was determined by immunofluorescence.Results: PD-L1 expression was detected within peripheral circulating cells associated with malignancy (CCAM) in 26 of 112 (23%) non-small cell lung cancer patients. Two distinct populations of nucleated, nonhematolymphoid, PD-L1-expressing cells were identified; cytokeratin positive (CK+, PD-L1+, CD45-) and cytokeratin negative (CK-, PD-L1+, CD45-) cells, both with cytomorphometric features (size, nuclear-to-cytoplasm ratio) consistent with tumor cells. Patients with >1.1 PD-L1(+) cell/mL (n = 14/112) experienced worse overall survival than patients with ≤1.1 PD-L1(+) cell/mL (2-year OS: 31.2% vs. 78.8%, P = 0.00159). In a Cox model adjusting for stage, high PD-L1(+) cell burden remained a significant predictor of mortality (HR = 3.85; 95% confidence interval, 1.64-9.09; P = 0.002).Conclusions: PD-L1 expression is detectable in two distinct cell populations in the peripheral blood of lung cancer patients and is associated with worse survival.Impact: These findings could represent a step forward in the development of minimally invasive liquid biopsies for the profiling of tumors. Cancer Epidemiol Biomarkers Prev; 26(7); 1139-45. ©2017 AACR.
| S-EPMC5500408 | biostudies-literature
Project description:In the tumor microenvironment, local immune dysregulation is driven in part by macrophages and dendritic cells that are polarized to a mixed proinflammatory/immune-suppressive phenotype. The unfolded protein response (UPR) is emerging as the possible origin of these events. Here we report that the inositol-requiring enzyme 1 (IRE1α) branch of the UPR is directly involved in the polarization of macrophages in vitro and in vivo, including the up-regulation of interleukin 6 (IL-6), IL-23, Arginase1, as well as surface expression of CD86 and programmed death ligand 1 (PD-L1). Macrophages in which the IRE1α/X-box binding protein 1 (Xbp1) axis is blocked pharmacologically or deleted genetically have significantly reduced polarization and CD86 and PD-L1 expression, which was induced independent of IFNγ signaling, suggesting a novel mechanism in PD-L1 regulation in macrophages. Mice with IRE1α- but not Xbp1-deficient macrophages showed greater survival than controls when implanted with B16.F10 melanoma cells. Remarkably, we found a significant association between the IRE1α gene signature and CD274 gene expression in tumor-infiltrating macrophages in humans. RNA sequencing (RNASeq) analysis showed that bone marrow-derived macrophages with IRE1α deletion lose the integrity of the gene connectivity characteristic of regulated IRE1α-dependent decay (RIDD) and the ability to activate CD274 gene expression. Thus, the IRE1α/Xbp1 axis drives the polarization of macrophages in the tumor microenvironment initiating a complex immune dysregulation leading to failure of local immune surveillance.
| S-EPMC7307794 | biostudies-literature
Project description:Blocking the binding between the PD-1 and PD-L1 has been reported to produce antitumor responses. The MET/HGF axis appears to be another signaling pathway frequently altered in small cell lung cancer (SCLC). Our study was aimed to investigate the expression and prognostic roles of PD-L1 and c-MET in SCLC.The expression levels of PD-L1 and c-MET were evaluated by immunohistochemical analysis in 83 SCLC specimens. Survival analysis was performed using the Kaplan-Meier method.Of the SCLC specimens, 51.8% and 25.3% exhibited positivity for PD-L1 and c-MET, respectively. Higher PD-L1 expression in tumor specimens was significantly correlated with a limited disease (LD) stage, normal levels of serum lactate dehydrogenase (LDH) and neuron-specific enolase (NSE). No association was found between the levels of c-MET and PD-L1 expression or between c-MET expression and other clinical characteristics. SCLC patients with PD-L1-positive tumors showed significantly longer overall survival (OS) than patients with PD-L1-negative tumors (17.0 vs 9.0, p=0.018). Conversely, those with positive c-MET expression exhibited a shorter OS trend (12.0 vs 15.0, p=0.186). However, sub-analysis of LD-stage patients revealed longer OS among the c-MET-negative group (25.0 vs 14.0; p=0.011). The OS of patients with positivity for both PD-L1 and c-MET showed no significant difference compared with other patients (p=0.17). According to multivariate analyses, neither PD-L1 nor c-MET immunoreactivity was a prognostic factor.Expression of PD-L1 was correlated with LD stage and might serve as a prognostic for better OS in SCLC patients. In LD-stage patients, high c-MET expression might be predictive of a poor outcome.
| S-EPMC5589556 | biostudies-literature
Project description:Purpose Targeting of the PD-1/PD-L1 signalling pathway is a promising treatment strategy in several cancers. The aim of this study was to assess the expression of PD-L1 on tumour cells and tumour-infiltrating lymphocytes (TILs) in gastric cancer (GC) and its prognostic impact. Materials and Methods A total of 240 patients who were diagnosed with GC at Sun Yat-sen University Cancer Centre (SYSUCC) from May 2008 to December 2013 were included in this study. PD-L1 expression was detected by immunohistochemistry (IHC) in all GC tumour specimens. The Cox proportional hazard regression model was used to assess the association between PD-L1 expression and overall survival (OS). Results The positive rates of PD-L1 expression on tumour cells and TILs were 74.8% and 65.8%, respectively. Patients with poor tumour differentiation had higher positive rates of PD-L1 expression on tumour cells (p=0.023). There was no significant association between PD-L1 expression on tumour cells and other clinicopathological data. In TILs, PD-L1 expression was significantly higher in patients who underwent surgery (p=0.031) and were in the late stage (p=0.021) than those without surgery and in the early stage. Patients with positive PD-L1 expression on TILs had a significantly shorter five-year OS than those with negative PD-L1 expression (14.2 vs 18.3; p=0.001); therefore, PD-L1 expression on TILs is an independent prognostic factor. However, PD-L1 expression on tumour cells is not associated with OS (p=0.945). Conclusion Our findings suggest that PD-L1 expression on TILs may be a predictive factor for immunotherapy of PD-1/PD-L1 pathway inhibitors.
| S-EPMC5535713 | biostudies-other
Project description:PURPOSE:Immune-checkpoint inhibitors (ICI) have improved the survival of patients with non-small cell lung cancer (NSCLC). However, only a subset of patients benefit from ICIs, and the role of PD-L1 as predictive biomarker is still debated. A plasma immune-related miRNA-signature classifier (MSC) was established in lung cancer screening settings to identify the lethal form of the disease in early stages. In this exploratory study, we tested the efficacy of the MSC as prognostic marker in patients with advanced NSCLC treated with ICIs. EXPERIMENTAL DESIGN:The MSC risk level was prospectively assessed in a consecutive series of 140 patients with NSCLC before starting treatment with ICIs. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in strata of PD-L1 and MSC alone or combined were considered as endpoints. Multiple plasma samples to monitor MSC risk level during treatment were also profiled. RESULTS:Adequate tissue and plasma samples were available from 111 (79%) and 104 (75%) patients with NSCLC, respectively. MSC risk level was associated with ORR (P = 0.0009), PFS [multivariate HR = 0.31; 95% confidence interval (CI), 0.17-0.56; P = 0.0001], and OS (multivariate HR = 0.33; 95% CI, 0.18-0.59; P = 0.0002). The combination of MSC and PD-L1 stratified patients into three risk groups having 39%-18%-0% 1-year PFS (P < 0.0001) and 88%-44%-0% 1-year OS (P < 0.0001), according to the presence of 2-1-0 favorable markers. During treatment, MSC risk level decreased or remained low until tumor progression in patients with responsive or stable disease. CONCLUSIONS:The plasma MSC test could supplement PD-L1 tumor expression to identify a subgroup of patients with advanced lung cancer with worse ORR, PFS, and OS in immunotherapy regimens.
| S-EPMC6445748 | biostudies-literature
Project description:Data describing relationships between the tumor immune microenvironment and patient outcome are limited for esophageal squamous cell cancer (ESCC). The present study investigated the prognostic values of programmed death-ligand 1 (PD-L1) expression and CD8+ or forkhead box protein 3+ (FOXP3+) tumor-infiltrating lymphocytes (TILs) in 133 pathological T3N0M0 stage ESCC patients who underwent radical resection without neoadjuvant or adjuvant therapy. CD8+ and FOXP3+ TIL densities as well as PD-L1 levels in tumor cells and lymphocytes, were assessed through immunohistochemical staining. Patient survival was not associated with CD8+ or FOXP3+ TILs alone, but PD-L1 expression and the CD8+/FOXP3+ ratio were independent predictors of both disease-free and overall survival. PD-L1 expression correlated with age (p = 0.029), tumor length (p < 0.001), tumor differentiation status (p = 0.002) and reduced intratumoral CD8+ TIL density (p < 0.001). Our results suggest pT3N0M0 ESCC clinical outcomes correlate with CD8+ and FOXP3+ TIL densities and PD-L1 levels. Moreover, an intrinsic mechanism for induction of PD-L1 overexpression may be occurring during early tumor oncogenesis. This information may be useful for stratifying patients and guide the application of checkpoint blockade therapy in ESCC.
| S-EPMC5342092 | biostudies-literature
Project description:BackgroundMost patients with methotrexate-associated lymphoproliferative disorder (MTX-LPD) show diffuse large B-cell lymphoma (DLBCL) or classic Hodgkin lymphoma (CHL) types. Patients with MTX-LPD often have spontaneous remission after MTX discontinuation, but chemotherapeutic intervention is frequently required in patients with CHL-type MTX-LPD. In this study, we examined whether programmed cell death-ligand 1 (PD-L1) expression levels were associated with the prognosis of MTX-LPD after MTX discontinuation.MethodsA total of 72 Japanese patients diagnosed with MTX-LPD were clinicopathologically analyzed, and immunohistochemical staining of PD-L1 was performed in 20 DLBCL-type and 24 CHL-type MTX-LPD cases to compare with the clinical course.ResultsPD-L1 was expressed in 5.0% (1/20) of patients with DLBCL-type MTX-LPD, whereas it was expressed in 66.7% (16/24) of the patients with CHL-type MTX-LPD in more than 51% of tumor cells. Most CHL-type MTX-LPD patients with high PD-L1 expression required chemotherapy owing to exacerbations or relapses after MTX discontinuation. However, no significant differences in clinicopathologic findings at diagnosis were observed between PD-L1 high- and low-expression CHL-type MTX-LPD.ConclusionPD-L1 expression was significantly higher in patients with CHL-type than DLBCL-type MTX-LPD, suggesting the need for chemotherapy in addition to MTX discontinuation in CHL-type MTX-LPD patients to achieve complete remission. No association was observed between PD-L1 expression levels and clinical findings at diagnosis, suggesting that PD-L1 expression in tumor cells influences the pathogenesis of CHL-type MTX-LPD after MTX discontinuation.
| S-EPMC8729050 | biostudies-literature
Project description:Programmed death ligand 1 (PD-L1) expression is a predictive biomarker of the success of PD-1/PD-L1 inhibitor therapy for patients with advanced non-small cell lung cancer (NSCLC) but its role as a prognostic marker for early-stage resectable NSCLC remains unclear. We studied gene expression levels of immune-related genes PD-1, PD-L1, PD-L2, IDO-1, IDO-2 and INFγ in tumor tissue of surgically resected NSCLC and correlated the finding with clinicopathological features and patient outcomes. A total of 191 consecutive early-stage NSCLC patients who underwent curative pulmonary resection were studied. The mRNA expression levels of immune-related genes were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RT2 Profiler PCR Arrays (Qiagen). PD-1, PD-L2 and IDO-2 gene expression levels were significantly higher in patients with squamous histology (p = 0.001, p = 0.021 and p < 0.001; respectively). PD-1, PD-L1 and IDO-2 gene expression levels were significantly higher in patients with higher stage (p = 0.005, p = 0.048 and p = 0.002, respectively). The univariate analysis for recurrence-free survival (RFS) and overall survival (OS) showed that patients with higher levels of three-genes (PD-L1/PD-L2/INFγ) (hazard ratio (HR)) 1.90 (95% confidence interval (CI), 1.13-3.21), p = 0.015) were associated with a worse RFS, while patients with higher levels of both genes (PD-L1/IDO-2) or (PD-L2/IDO-1) were associated with a worse OS (HR 1.63 95% CI, 1.06-2.51, p = 0.024; HR 1.54 95% CI, 1.02-2.33, p = 0.04; respectively). The multivariate interaction model adjusted for histology and stage confirmed that higher levels of three genes (PD-L1/PD-L2/INFγ) were significantly associated with worse RFS (HR 1.98, p = 0.031) and higher levels of both genes (PD-L1/IDO-2) and (PD-L2/IDO-1) with worse OS (HR 1.98, p = 0.042, HR 1.92, p = 0.022). PD-L1/IDO-2 and PD-L2/IDO-1 co-expression high levels are independent negative prognostic factors for survival in early NSCLC. These features may have important implications for future immune-checkpoint therapeutic approaches.
| S-EPMC7918978 | biostudies-literature