PD-L1 and PD-1 expression correlate with prognosis in extrahepatic cholangiocarcinoma.
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ABSTRACT:
SUBMITTER: Ma K
PROVIDER: S-EPMC5494943 | biostudies-other | 2017 Jul
REPOSITORIES: biostudies-other
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Project description:Extrahepatic cholangiocarcinoma (eCCA) has a poor prognosis. Although the possibility of immunotherapy has been studied, immune checkpoint molecules such as programmed death ligand 1 (PD-L1) in eCCA are not well understood. Epithelial-mesenchymal transition (EMT) has recently been shown to regulate PD-L1 expression. Our aims were to assess the clinicopathological significance of tumor-infiltrating lymphocytes (TILs) and tumor PD-L1 expression in eCCA and to compare these immune responses with EMT marker expression. In this retrospective study, we conducted immunohistochemical analyses for 117 patients with eCCA. We stained for CD4, CD8, Foxp3, and PD-L1 as markers reflecting local immune responses, and for E-cadherin, N-cadherin, vimentin, ZEB1, ZEB2, SNAIL, and TWIST as markers associated with EMT. High numbers of CD4+ and CD8+ TILs correlated with node-negative (P = 0.009 and P = 0.046, respectively) and low SNAIL expression (P = 0.016 and P = 0.022, respectively). High PD-L1 expression was associated with poor histopathological classification (P = 0.034), and low E-cadherin (P = 0.001), high N-cadherin (P = 0.044), high vimentin (P < 0.001) and high ZEB1 (P = 0.036) expression. Multivariate analysis showed that CD4+ TILs, PD-L1 expression and N-cadherin expression were independent prognostic factors (hazard ratio (HR) = 0.61; 95% confidence interval (CI) = 0.38-1.00; HR=4.27; 95% CI = 1.82-9.39; HR = 2.20; 95% CI = 1.18-3.92, respectively). These findings could help to identify potential biomarkers for predicting not only the prognosis, but also the therapeutic response to immunotherapy for eCCA.
| S-EPMC5929444 | biostudies-literature
Project description:ObjectiveImmunotherapy targeting the programmed cell death protein-1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) pathway has been observed to be efficient in several solid tumors. We aim to investigate the prognostic significance of PD-1/PD-L1 expression profile in intrahepatic cholangiocarcinoma (ICC).Materials and methodsWe investigated the expression of PD-1, PD-L1, CD8+ T cells, and CD68+ macrophages in paired tumor and adjacent normal tissues from 322 ICC patients using tyramide signal amplification (TSA)-based multiplexed immunohistochemistry.ResultsWe found that high proportion of tumor-infiltrating CD8+ PD-1High within CD8+ PD-1+ T cells significantly correlated with advanced TNM stage (P = 0.035). ICC patients with high proportion of CD8+ PD-1High in CD8+ PD-1+ had worse postoperative survival than low proportion patients (P = 0.0037), which was an independently prognostic factor for OS (P = 0.025,). The density of CD68+ PD-L1+ significantly and positively correlated with the density of CD8+ PD-1High (P < 0.0001, r = 0.5927). The proportion of CD68+ PD-L1+ within CD68+ ICC was the risk factor for OS and TTR but not an independently factor for prognosis. The CD68+ PD-L1+ macrophages and CD8+ PD-1High T cells may cooperatively play a role in inhibiting anti-tumor immunity.ConclusionCD68+ PD-L1+ macrophages and CD8+ PD-1High T cells predict unfavorable prognosis, which could also bring new progress about immune target therapy in ICC research.
| S-EPMC7686719 | biostudies-literature
Project description:BackgroundTherapeutic approaches for extrahepatic cholangiocarcinoma (EHCC) are limited, due to insufficient understanding to biomarkers related to prognosis and drug response. Here, we comprehensively assess the molecular characterization of EHCC with clinical implications.MethodsWhole-exome sequencing (WES) on 37 tissue samples of EHCC were performed to evaluate genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI).ResultsMutation of KRAS (16%) was significantly correlated to poor OS. ERBB2 mutation was associated with improved OS. ERBB2, KRAS, and ARID1A were three potentially actionable targets. TMB ≥10 mutations per megabase was detected in 13 (35.1%) cases. Six patients (16.2%) with MSIsensor scores ≥10 were found. In multivariate Cox analysis, patients with MSIsensor sore exceed a certain threshold (MSIsensor score ≥0.36, value approximately above the 20th percentile as thresholds) showed a significant association with the improved OS (HR = 0.16; 95% CI: 0.056-0.46, p < 0.001), as well as patients with both TMB ≥3.47 mutations per megabase (value approximately above the 20th percentile) and MSIsensor score ≥0.36.ConclusionsTMB and MSI are potential biomarkers associated with better prognosis for EHCC patients. Furthermore, our study highlights important genetic alteration and potential therapeutic targets in EHCC.
| S-EPMC10652350 | biostudies-literature
Project description:While the prognosis of gastric cancer (GC) remains poor, PD-1 and PD-L1/L2 are promising prognostic biomarkers. We evaluated PD-1 and PD-L1/L2 expression in tumor cells (TCs) and tumor-infiltrating immune cells (TIICs). We determined the Helicobacter pylori (Hp) and Epstein-Barr virus (EBV) infection status in a GC cohort (n=340), then analyzed the relationship between the expression of PD-1, PD-L1/L2 and GC prognosis. We found that PD-1, PD-L1, and PD-L2 mRNA levels were up-regulated in GC tissues, and were positively correlated with one another (P=0.043, P=0.008 and P=0.035). PD-1 protein expression in TIICs was observed in 22.6% of GC patients. The PD-L1 and PD-L2 positivity rates were 40.3% and 53.8% in TCs, respectively, and 60.0% and 60.9% in TIICs, respectively. PD-L1 was up-regulated in EBV-infected GC patients in both TCs (P=0.009) and TIICs (P=0.003). Hp status was not associated with PD-1 or PD-L1/PD-L2 expression. In TIICs, PD-L1 expression was independently associated with better GC prognosis (HR=0.72, 95%CI: 0.53-0.99). Co-expression of PD-1 and PD-L1, but not PD-L2, was a favorable prognostic marker that indicated a dose effect on the mortality risk of GC patients (P-value for trend=0.005). Comprehensive evaluation of PD-1 and PD-L1 in TCs and TIICs could help predict the prognosis of gastric cancers, as well as reveal patients who might benefit from targeted treatment.
| S-EPMC5609984 | biostudies-literature
Project description:The protein 14-3-3? interacts with Trp53 to maintain G2 arrest and thus regulates the cell cycle. Though dysfunction of 14-3-3? caused by hyper-methylation of CpG islands was reported in several carcinomas, the exact role of this protein in the development of extrahepatic cholangiocarcinoma has not been fully elucidated. Here, we aim at investigating the clinical relevance between 14-3-3? and human extrahepatic cholangiocarcinoma. We collected extrahepatic cholangiocarcinoma specimens of 65 patients in Beijing Chao Yang Hospital and evaluated their 14-3-3? expression using immunohistochemistry. We categorized the patients into different subgroups according to clinic pathological factors, such as sex, age, tumor size, pathological classification, lymph node metastasis status, tumor stage, and serum markers including CEA, CA-242, or CA19-9, and further evaluated the correlation between 14-3-3? expression and these potential prognostic factors. As a result, we detected 14-3-3? expression in 53 out of 65 specimens (81.5%), and the expression was positively correlated with TNM stage, lymph node metastasis, and overall survival. Our results suggest that 14-3-3? serves as an oncogenic driver in extrahepatic cholangiocarcinoma tumorigenesis rather than a cell cycle regulator; the overexpression of 14-3-3? might be frequently acquired by tumor cells to escape appropriate cell cycle regulation. Thus, 14-3-3? could be a potential target for extrahepatic cholangiocarcinoma diagnosis and therapy.
| S-EPMC7321506 | biostudies-literature
Project description:Background: Recently, blockade of immune checkpoint has emerged as one of the most potential treatments for solid tumors. Programmed cell death ligand 1(PD-L1), a member of the B7 family of molecules, plays a crucial role in tumor immunobiology. However, the prognostic significance of PD-L1 in cholangiocarcinoma (CCA) patients remains controversial. This study aimed to inquire into the prognostic and clinicopathological significance of PD-L1 in CCA via a meta-analysis. Methods: We searched PubMed, the Cochrane Library, Embase, Web of Science and Google Scholar up to April 2019, regardless of the region or language, for studies on the correlation between clinicopathology/prognosis and PD-L1 in patients with CCA. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to investigate the prognostic significance of PD-L1 expression in cholangiocarcinoma. The odds ratios (ORs) were also determined to explore the association between PD-L1 expression and clinicopathological features. Results: Our meta-analysis included 11 studies with 1,066 patients. The meta-analysis of these studies indicated a trend that high PD-L1 expression indicated a poor OS, but the result was not statistically significant (HR = 1.62, 95% CI [0.98-2.68], p = 0.063). For DFS, although the pooled result is not statistically significant, it trends toward being significant that high PD-L1 expression indicated improved DFS (HR = 0.80, 95% CI [0.62, 1.04], p = 0.092). In subgroup analyses, the results were not consistent across the subgroups that were divided based on the publication year (before 2018: HR = 1.92, 95% CI [1.34-2.75], p < 0.001; after 2018: HR = 1.42, 95% CI [0.70-2.89], p = 0.335). Moreover, PD-L1 expression in TCs significantly correlated with the AJCC TNM stage of CCA (OR = 0.52, 95% CI [0.27, 0.99], p = 0.09). Conclusion: Our meta-analyses revealed that PD-L1 expressed in TCs was significantly correlated with the AJCC TNM stage of CCA. Based on the included studies, we found that PD-L1 indeed expressed in both TCs and ICs in CCA patients, raising the possibility of the use of anti-PD-1/PD-L1 therapy for CCA patients. In contrast, expression of PD-L1 did not seem to be associated with patient outcome in our study. The prognostic role of PD-L1 in CCA demands further investigation.
| S-EPMC6759577 | biostudies-literature
Project description:PD-L1 expression in melanoma correlates with response to PD-1 pathway-blocking antibodies. Aberrant tumor-cell PD-L1 expression may be oncogene driven and/or induced by IFN?. Melanomas express PD-L1 in association with tumor-infiltrating lymphocytes (TIL), but the potential contribution of the BRAF V600E mutation (BRAFmut) to induced PD-L1 expression has not been determined. Fifty-two archival melanocytic lesions were assessed for PD-L1 expression, TIL infiltration, and BRAFmut simultaneously. IFN?-induced PD-L1 expression in cultured melanomas was assessed in parallel according to BRAF status. Melanocyte PD-L1 expression was observed in 40% of specimens, and BRAFmut was observed in 42% of specimens, but no significant concordance was found between these variables. Almost all melanocytes displaying PD-L1 expression were observed to be adjacent to TILs, irrespective of BRAF status. TIL(-) lesions were not more likely to be associated with BRAFmut, when compared with TIL(+) lesions. Baseline expression of PD-L1 by melanoma cell lines was virtually nil, regardless of BRAFmut status, and the intensity of IFN-induced PD-L1 expression in melanoma cell lines likewise did not correlate with BRAF mutational status. PD-L1 expression in melanocytic lesions does not correlate with the BRAFmut. Thus, distinct populations of melanoma patients will likely benefit from BRAF inhibitors versus PD-1 pathway blockade.
| S-EPMC4324161 | biostudies-literature
Project description:BackgroundImmunotherapy can become a crucial therapeutic option to improve prognosis for lung cancer patients. First clinical trials with therapies targeting the programmed cell death receptor PD-1 and its ligand PD-L1 have shown promising results in several solid tumors. However, in lung cancer the diagnostic, prognostic and predictive value of these immunologic factors remains unclear.MethodThe impact of both factors was evaluated in a study collective of 321 clinically well-annotated patients with non-small lung cancer (NSCLC) using immunohistochemistry.ResultsPD-1 expression by tumor infiltrating lymphocytes (TILs) was found in 22%, whereas tumor cell associated PD-L1 expression was observed in 24% of the NSCLC tumors. In Fisher's exact test a positive correlation was found for PD-L1 and Bcl-xl protein expression (p = 0.013). Interestingly, PD-L1 expression on tumor cells was associated with improved overall survival in pulmonary squamous cell carcinomas (SCC, p = 0.042, log rank test), with adjuvant therapy (p = 0.017), with increased tumor size (pT2-4, p = 0.039) and with positive lymph node status (pN1-3, p = 0.010). These observations were confirmed by multivariate cox regression models.ConclusionOne major finding of our study is the identification of a prognostic implication of PD-L1 in subsets of NSCLC patients with pulmonary SCC, with increased tumor size, with a positive lymph node status and NSCLC patients who received adjuvant therapies. This study provides first data for immune-context related risk stratification of NSCLC patients. Further studies are necessary both to confirm this observation and to evaluate the predictive value of PD-1 and PD-L1 in NSCLC in the context of PD-1 inhibition.
| S-EPMC4552388 | biostudies-literature
Project description:The associations between programmed cell death ligand 1 (PD-L1) and the prognosis of various cancers have always been a research topic of considerable interest. However, the prognostic value of PD-L1 in breast cancer patients remains a controversial subject. We aimed to assess the association between PD-L1 protein expression and clinicopathological features and the impact of this relationship on breast cancer survival. We performed a systematic search of the PubMed, EMBASE, and Cochrane Library databases to determine the correlations among PD-L1 expression, clinicopathological features and overall survival (OS). A total of 5 studies containing 2,546 cases were included in the analysis. The combined hazard ratio (HR) and its 95% confidence interval (CI) for OS were 1.76 (95% CI 1.09-2.82; P=0.02) for patients with tumors exhibiting PD-L1 overexpression. The pooled odds ratios (ORs) indicated that PD-L1 expression was associated with positive lymph node metastasis, higher histological grades, estrogen receptor (ER)-negativity, and triple-negative breast cancer (TNBC). Our findings indicate that PD-L1 expression is a promising biomarker for the prognosis of breast cancer, and may be helpful to clinicians aiming to select the appropriate immunotherapy for breast cancer.
| S-EPMC5458212 | biostudies-literature
Project description:BackgroundThe prognostic implications of tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are poorly studied in hematologic malignancies.ObjectivesThis study aimed to better understand the characteristics and prognostic value of TMB and PD-1/PD-L1 in hematologic malignancies.DesignThis real-world study was conducted among patients with hematologic malignancies who had next-generation sequencing (NGS) (Foundation Medicine) at the University of California San Diego Moores Cancer Center (2014-2018).MethodsTMB was measured by NGS. PD-L1 expression (tumor proportion score, TPS) was measured by immunohistochemistry (classified as high (⩾50%), low (1-49%), and negative (<1%)). Data was curated from the electronic medical records.ResultsIn 388 evaluable patients, the most common diagnoses were B-cell non-Hodgkin lymphoma (NHL) (35%) and Philadelphia chromosome-negative myeloproliferative disorders (16%). Median TMB was 1.6 mutations/Mb (range, 0-46.83). Forty-eight patients (12%) had TMB ⩾10 mutations/Mb, 90% of which were B-cell or T-cell NHL. In 85 samples with available PD-L1 scores, 11 were high; 26, low; and 48, no tumor cell expression. PD-L1 TPS positive (⩾1%) was most common in T-cell NHL (7/9 (77%) cases) followed by B-cell NHL (21/51 (41%) cases). TMB ⩾4 mutations/Mb and PD-L1 score ⩾1% were significantly associated with shorter overall survival (OS) from diagnosis, with hazard ratio (HR) = 1.46 (p = 0.02, 95% confidence interval (CI) 1.05-2.03) and HR = 2.11 (p = 0.04, 95% CI 1.04-4.30), respectively; the relationship was more pronounced when PD-L1 ⩾50% versus <50% was used (HR = 2.80, p = 0.02, 95% CI 1.19-6.59). Higher TMB and higher PD-L1 positivity correlation were significant but weak (Pearson correlation coefficient R 2 = 0.04, p = 0.04).ConclusionTMB ⩾4 mutations/Mb and positive PD-L1 TPS are poor prognostic factors, correlating with shorter OS across hematologic malignancies.Trial registrationClinicalTrials.gov NCT02478931.
| S-EPMC11363031 | biostudies-literature