Clinical implications of heterogeneity in PD-L1 immunohistochemical detection in hepatocellular carcinoma: the Blueprint-HCC study.
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ABSTRACT:
SUBMITTER: Pinato DJ
PROVIDER: S-EPMC6738063 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Accumulating studies suggest that targeting epigenetic modifications could improve the efficacy of tumor immunotherapy; however, the mechanisms underlying this phenomenon remain largely unknown. Here, we investigated the ability of the epigenetic modifier, enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), to regulate the expression of immune checkpoint inhibitor, programmed death-1 ligand 1 (PD-L1) in hepatocellular carcinoma (HCC). METHODS:Immunohistochemistry and multiplex immunofluorescence staining were performed to analyze the expression and correlation of EZH2 and PD-L1 in HCC tissues. Immunoblotting, quantitative real-time PCR, flow cytometry, chromatin immunoprecipitation, and dual-luciferase reporter gene assays were performed to evaluate the regulatory roles of EZH2 on PD-L1 expression. RESULTS:In vitro cell experiments revealed that EZH2 negatively regulated the PD-L1 expression of hepatoma cell lines in IFN?-dependent manner. Mechanistic studies demonstrated that EZH2 could suppress PD-L1 expression by upregulating the H3K27me3 levels on the promoters of CD274 (encoding PD-L1) and interferon regulatory factor 1 (IRF1), an essential transcription factor for PD-L1 expression, without affecting the activation of the IFN?-signal transducer and activator of transcription 1 (STAT1) pathway. Clinical samples from HCC patients with immune-activated microenvironments showed negative correlations between EZH2 and PD-L1 expression in hepatoma cells. Multivariate Cox analysis demonstrated that the combination of EZH2 and PD-L1 was an independent prognostic factor for both OS and RFS for patients with HCC. CONCLUSIONS:The epigenetic modificator EZH2 can suppress the expression of immune checkpoint inhibitor PD-L1 by directly upregulating the promoter H3K27me3 levels of CD274 and IRF1 in hepatoma cells, and might serve as a potential therapeutic target for combination of immunotherapy for immune-activated HCC.
| S-EPMC6854886 | biostudies-literature
Project description:BackgroundAnti-programmed cell death-1(anti-PD1) treatment has shown promising antitumor efficacy in patients with advanced hepatocellular carcinoma (HCC). This study sought to explore the functional significance of programmed death ligand-1 (PD-L1) expression in tumor cells in the tumor microenvironment.MethodsThe mouse liver cancer cell line BNL-MEA was transfected with PD-L1 plasmids and stable clones expressing PD-L1 were selected. An orthotopic HCC model was generated by implanting the cells into the subcapsular space of BALB/c mice. Cell growth features were measured by proliferation assay, colony formation, flow cytometry (in vitro), ultrasonography, and animal survival (in vivo). The changes in T-cell function were examined by cytokine assay, expression of T-cell related genes, and flow cytometry. The efficacy of anti-PD1 therapy was compared between the parental and PD-L1-expressing tumors.ResultsPD-L1 expression did not affect growth characteristics of BNL-MEA cells but downregulated the expression of genes related to T-cell activation in the tumor microenvironment. Co-culture of PD-L1-expressing BNL-MEA cells with CD8+ T cells reduced T-cell proliferation and expression of cytokines IFNγ and TNFα. Tumors with PD-L1 expression showed better response to anti-PD1 therapy and depletion of CD8+ T cells abolished the antitumor effect. The difference in treatment response between parental and PD-L1-expressing tumors disappeared when a combination of anti-PD1 and sorafenib was given.ConclusionsPD-L1 expression in HCC cells may inhibit T-cell function in the liver tumor microenvironment. Anti-PD1 therapy appeared more effective in PD-L1-expressing than nonexpressing tumors, but the difference was diminished by the addition of sorafenib.
| S-EPMC6547269 | biostudies-literature
Project description:The interpatient variability of tumor proteomes has been investigated on a large scale but many tumors display also intratumoral heterogeneity regarding morphological and genetic features. It remains largely unknown to what extent the local proteome of tumors intrinsically differs. Here, we used hepatocellular carcinoma as a model system to quantify both inter- and intratumor heterogeneity across human patient specimens with spatial resolution. We defined proteomic features that distinguish neoplastic from the directly adjacent nonneoplastic tissue, such as decreased abundance of NADH dehydrogenase complex I. We then demonstrated the existence of intratumoral variations in protein abundance that re-occur across different patient samples, and affect clinically relevant proteins, even in the absence of obvious morphological differences or genetic alterations. Our work demonstrates the suitability and the benefits of using mass spectrometry-based proteomics to analyze diagnostic tumor specimens with spatial resolution. Data are available via ProteomeXchange with identifier PXD007052.
| S-EPMC5880102 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the fifth most common cancer and accounts for 8 [...].
| S-EPMC7763211 | biostudies-literature
Project description:Currently, four immunohistochemical assays are registered with the US Food and Drug Administration to detect the expression of PD-L1. We investigated the PD-L1 expression in thymic carcinomas using these four diagnostic assays. The cases of 53 patients were reviewed and their specimens were subjected to four PD-L1 assays with different antibodies (SP142, SP263, 22C3, and 28-8). The PD-L1 expression in tumor cells (TCs) and immune cells (ICs) was evaluated. In TCs, the four assays showed similar scores in each case. Histopathologically, high TC scores were observed in squamous cell carcinomas (SqCCs). Meanwhile, there were no significant relationships among the IC scores in the four assays. In SqCCs, the high expression of PD-L1 (defined as ?50% TC score) in TCs tended to be associated with early stage cancer. The patients with high expression levels of PD-L1 tended to show longer overall survival in the 22C3 assays (p=0.0200). In thymic carcinomas, the staining pattern showed high concordance among the four assays when TCs - rather than ICs - were stained. High PD-L1 positivity in TCs, especially in SqCCs, indicated that PD-1/PD-L1 targeted therapy may be a promising therapeutic approach.
| S-EPMC5805531 | biostudies-literature
Project description:BackgroundCervical small cell neuroendocrine carcinoma (SCNC) is a rare and aggressive disease that lacks a standard treatment strategy or effective methods of targeted therapy. PD-L1 inhibitors for DNA mismatch repair system-deficient (dMMR) tumors and neurotrophin receptor tyrosine kinase (NTRK) inhibitors offer potential pan-cancer treatments.MethodsImmunohistochemistry was employed as the main detection method, and any NTRK positive cases, identified by immunohistochemistry, were further submitted for evaluation by fluorescence in situ hybridization (FISH) and real-time polymerase chain reaction (RT-PCR) methods.ResultsForty-six patients were enrolled. Positive PD-L1 expression was seen in 22 of the 43 patients (51.16%) with an average combined positive score of 6.82. PD-L1-positive patients were more likely to have a higher proliferation rate in the tumor, and they experienced less recurrence and death (p = 0.048 and 0.033, respectively) compared with the patients with negative PD-L1 expression. However, in the multivariate analysis, none of the clinical parameters was associated with the expression of PD-L1. There was no association between PD-L1 expression and disease recurrence or overall survival in the Kaplan-Meier analysis. All cases were found to be MMR-stable and lacked NTRK gene fusion. However, pan-Trk expressed in 14 (32.56%) of the 43 tested cases, but FISH and RT-PCR failed to confirm any positive fusion signals in IHC-positive cases.ConclusionsPD-L1 may be an effective therapeutic target for cervical SCNC. Cervical SCNC is a MMR-stable tumor and lacks NTRK gene fusion. IHC isn't a reliable method in the detection of NTRK gene fusion in cervical SCNC.
| S-EPMC8566736 | biostudies-literature
Project description:Response to anti-PD-L1/PD-1 immunotherapy correlates with PD-L1 expression in breast cancer. However, the prevalence of PD-L1 positive breast cancer is variable, which could be due to differences in the population/cohort of patients tested or the preservation/detection technology used. To investigate this variability, we examined the effect of two tissue preservation methods on PD-L1 immunohistochemical detection in breast cancer. We compared PD-L1 expression in patient-matched frozen (FR) and formalin-fixed paraffin-embedded (FFPE) tissues of breast cancer patients. PD-L1 expression was assessed using tumor proportion score (TPS, simply PD-L1 score), and case positivity was determined with PD-L1 score ≥5. In FFPE tissues, PD-L1 was positive in 7-10% of tested patients, depending on the antibody used. In patient-matched FR tissues, the same antibodies showed positive PD-L1 expression in 20-30% of cases. The impact of the antibody tested on the rate of PD-L1 positivity (% of PDL1 positive cases) was minor, as evident in the near perfect concordance between PD-L1 score obtained using the different antibodies whether tested in FR or FFPE tissues. However, there was a systematic drop by an average of 13-20% in the PD-L1 score obtained in FFPE tissues compared to their patient-matched FR tissues. In the tested patient-matched cohort, there was consistently a higher PD-L1 score in FR than FFPE tissues, regardless of the antibody used, demonstrating a significant effect on PD-L1 detection due to the preservation method. These findings should inspire further work to improve the sensitivity of PD-L1 detection and possibly search for more sensitive antibodies in FFPE tissues.
| S-EPMC8293136 | biostudies-literature
Project description: Not available
| S-DIXA-D-1017 | biostudies-other
Project description:Purpose: PD-L1 expression in the pretreatment tumor microenvironment enriches for response to anti-PD-1/PD-L1 therapies. The purpose of this study was to quantitatively compare the performance of five monoclonal anti-PD-L1 antibodies used in recent landmark publications.Experimental Design: PD-L1 IHC was performed on 34 formalin-fixed paraffin-embedded archival melanoma samples using the 5H1, SP142, 28-8, 22C3, and SP263 clones. The percentage of total cells (including melanocytes and immune cells) demonstrating cell surface PD-L1 staining, as well as intensity measurements/H-scores, were assessed for each melanoma specimen using a computer-assisted platform. Staining properties were compared between antibodies.Results: Strong correlations were observed between the percentage of PD-L1(+) cells across all clones studied (R2 = 0.81-0.96). When present, discordant results were attributable to geographic heterogeneity of the melanoma tissue section rather than differences in PD-L1 antibody staining characteristics. PD-L1 intensity/H-scores strongly correlated with percentage of PD-L1(+) cells (R2 > 0.78, all clones).Conclusions: The 5H1, SP142, 28-8, 22C3, and SP263 clones all demonstrated similar performance characteristics when used in a standardized IHC assay on melanoma specimens. Reported differences in PD-L1 IHC assays using these antibodies are thus most likely due to assay characteristics beyond the antibody itself. Our findings also argue against the inclusion of an intensity/H-score in chromogenic PD-L1 IHC assays. Clin Cancer Res; 23(16); 4938-44. ©2017 AACR.
| S-EPMC6175606 | biostudies-literature
Project description:BackgroundThere is a patent need to better characterize early-stage colorectal cancer (CRC) patients. PD-1 ligand (PD-L1) expression has been proposed as a prognostic factor but yields mixed results in different settings. The Consensus Molecular Subtype (CMS) classification has yet to be integrated into clinical practice. We sought to evaluate the prognostic value of PD-L1 expression overall and within CMS in early-stage colon cancer patients, in the hope of assisting treatment choice in this setting.MethodsTissue-microarrays were constructed from tumor samples of 162 stage II/III CRC patients. They underwent automatic immunohistochemical staining for PD-L1 and the proposed CMS panel. Primary endpoints were overall survival (OS) and disease-free survival (DFS).ResultsPD-L1 expression was significantly and independently associated with better prognosis (HR = 0.46 (0.26-0.82), p = 0.009) and was mostly seen in immune cells of the tumor-related stroma. CMS4 five-folds the risk of mortalitycompared with CMS1 (HR = 5.58 (1.36, 22.0), p = 0.034). In the subgroup CMS2/CMS3 analysis, PD-L1 expression significantly differentiated individuals with better OS (p = 0.004) and DFS (p < 0.001).ConclusionsOur study suggests that PD-L1 expression is an independent prognostic factor in patients with stage II/III colon cancer. Additionally, it successfully differentiates patients with better prognosis in the CMS2/CMS3 group and may prove significant for the clinical relevance of the CMS classification.
| S-EPMC8073668 | biostudies-literature