scholarly journals Programmed Death Ligand-1 (PD-L1) Is an Independent Negative Prognosticator in Western-World Gallbladder Cancer

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1682
Author(s):  
Thomas Albrecht ◽  
Fritz Brinkmann ◽  
Michael Albrecht ◽  
Anke S. Lonsdorf ◽  
Arianeb Mehrabi ◽  
...  
Keyword(s):  
Gallbladder Cancer ◽  
Immune Cells ◽  
Immune Cell ◽  
Western World ◽  
New Era ◽  
Poor Tumor Differentiation ◽  
Programmed Death ◽  
Cell Densities ◽  
Cell Death Protein ◽  
Immune Cell Score

Inhibition of the programmed cell death protein-1/ligand-1 (PD-1/PD-L1) axis has opened a new era in the treatment of solid cancers. However, there is no data on the expression and relevance of PD-L1 in Western gallbladder cancer (GBC). We assessed PD-L1 immunohistochemically in 131 GBC patients as Tumor Proportion Score (TPS), Immune Cell Score (IC) and Combined Positivity Score (CPS). Tumor cells expressed PD-L1 in a subset of 14.7% GBC patients at a TPS cut-off of 1%. Higher PD-L1 levels above 10% and 25% TPS were reached in 4.7% and 3.1% of GBC cases, respectively. At a 10% cut-off, TPS was associated with distinct histomorphological subtypes and correlated with poor tumor differentiation. Survival analysis revealed a TPS above 10% to be a highly significant and independent negative prognosticator in GBC. PD-L1 expression was associated with increased CD4+, CD8+ and PD-1+ immune cell densities. In 14.8% of the cases, scattered immune cells expressed T-cell immunoreceptor with Ig and ITIM domains (TIGIT), which was correlated to tumoral expression of its ligand CD155. We here show that a high PD-L1 expression confers a negative prognostic value in Western-world GBC and highlight the TIGIT/CD155 immune checkpoint as a potential new target for GBC immunotherapy.

scholarly journals Platelet PD-L1 suppresses anti-cancer immune cell activity in PD-L1 negative tumors

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Alexander B. Zaslavsky ◽  
M. P. Adams ◽  
X. Cao ◽  
T. Maj ◽  
J. E. Choi ◽  
...  
Keyword(s):  
Immune Cell ◽  
Checkpoint Inhibitor ◽  
Cell Activity ◽  
Antiplatelet Agents ◽  
Programmed Death ◽  
Anti Cancer ◽  
Platelet Binding ◽  
Cell Sources ◽  
The Impact ◽  
Cell Death Protein

Abstract Strategies that interfere with the binding of the receptor programmed cell death protein-1 (PD-1) to programmed death ligand-1 (PD-L1) have shown marked efficacy against many advanced cancers, including those that are negative for PD-L1. Precisely why patients with PD-L1 negative tumors respond to PD-1/PD-L1 checkpoint inhibition remains unclear. Here, we show that platelet-derived PD-L1 regulates the growth of PD-L1 negative tumors and that interference with platelet binding to PD-L1 negative cancer cells promotes T cell-induced cancer cytotoxicity. These results suggest that the successful outcomes of PD-L1 based therapies in patients with PD-L1 negative tumors may be explained, in part, by the presence of intra-tumoral platelets. Altogether, our findings demonstrate the impact of non-cancer/non-immune cell sources of PD-L1 in the tumor microenvironment in the promotion of cancer cell immune evasion. Our study also provides a compelling rationale for future testing of PD-L1 checkpoint inhibitor therapies in combination with antiplatelet agents, in patients with PD-L1 negative tumors.

scholarly journals Programmed Death Ligand 1: A Poor Prognostic Marker in Endometrial Carcinoma

Diagnostics ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 394
Author(s):  
Mianxin Chew ◽  
Yin Ping Wong ◽  
Norain Karim ◽  
Muaatamarulain Mustangin ◽  
Nurwardah Alfian ◽  
...  
Keyword(s):  
Endometrial Carcinoma ◽  
Immune Cells ◽  
Immune Cell ◽  
Tumour Cells ◽  
Health Concern ◽  
Major Health ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Incidence And Mortality ◽  
Gynaecologic Malignancy

Endometrial carcinoma is the only gynaecologic malignancy with a raising incidence and mortality, posing a major health concern worldwide. The upregulation of programmed death ligand 1 (PD-L1) on tumour cells causes T-cell suppression, which impedes antitumour immunity, promotes immune cell evasion and enhances tumour survival. The aim of this study was to evaluate PD-L1 expression in endometrial carcinoma and to correlate it with survival rate. A total of 59 cases of endometrial carcinoma were evaluated. Thirty-two cases of non-neoplastic endometrial tissue were included as control. PD-L1 immunohistochemistry was performed on all cases. PD-L1 expression was evaluated on tumour cells and immune cells. PD-L1 was positive in 62.7% (37/59) and 28.8% (17/59) of immune cells and tumour cells, respectively. PD-L1 expression in immune cells was significantly higher in endometrial carcinoma than in non-neoplastic endometrium (p < 0.001). Among the patients with endometrial carcinoma, PD-L1 expression in tumour cells was significantly higher in patients who died (10/15, 66.7%) compared to those who survived (7/44, 15.9%) (p < 0.001). It is noteworthy to point out that the expression of PD-L1 in tumour cells was significantly associated with a poor survival. This suggests that immunomodulation using PD-L1 inhibitors may be useful in advanced endometrial carcinoma.

Targeting PD-L1 Protein: Translation, Modification and Transport

2018 ◽  
Vol 20 (1) ◽  
pp. 82-91 ◽  
Author(s):  
Ran Wei ◽  
Libin Guo ◽  
Qingshui Wang ◽  
Jin Miao ◽  
Hang Fai Kwok ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Immune Cells ◽  
Functional Unit ◽  
Protein Translation ◽  
Effector T Cells ◽  
Programmed Death ◽  
A Cell ◽  
Cell Membrane Protein ◽  
L1 Protein ◽  
Cell Death Protein

Programmed death ligand 1 (PD-L1) is a cell membrane protein that binds to programmed cell death protein 1 (PD-1) on the effector T cells and transduces immunosuppressive signals. It is now clear that the expression of the PD-L1 protein on the tumor cell surface is critical for tumor cells to escape immunosuppression. At present, more attention is focused on the transcriptional regulation of PDL1 mRNA. However, PD-L1 protein is the functional unit involved in immunotherapy response. It is essential to deeply understand how this membrane protein is regulated post-transcriptionally in tumors and immune cells. In this review, we summarize the recent progress on the translation, modification and transport of PD-L1 protein.

scholarly journals Analytical Validation and Clinical Utility of an Immunohistochemical Programmed Death Ligand-1 Diagnostic Assay and Combined Tumor and Immune Cell Scoring Algorithm for Durvalumab in Urothelial Carcinoma

2018 ◽  
Vol 143 (6) ◽  
pp. 722-731 ◽  
Author(s):  
Magdalena Zajac ◽  
Anne-Marie Boothman ◽  
Yong Ben ◽  
Ashok Gupta ◽  
Xiaoping Jin ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Tumor Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Objective Response ◽  
Clinical Activity ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Sensitivity Specificity ◽  
Tumor Area

Context.— Clinical responses to anti–programmed death receptor-1 and anti–programmed death ligand-1 (PD-L1) agents are generally improved in patients with high PD-L1 expression compared with those with low/negative expression across several tumor types, including urothelial carcinoma. Objective.— To validate a PD-L1 immunohistochemical diagnostic test in urothelial carcinoma patients treated with the anti–PD-L1 monoclonal antibody durvalumab. Design.— The Ventana PD-L1 (SP263) assay was validated for intended use in urothelial carcinoma formalin-fixed, paraffin-embedded samples in studies addressing sensitivity, specificity, robustness, and precision, and implemented in study CD-ON-MEDI4736-1108 (NCT01693562). Efficacy was analyzed in patients classified according to prespecified PD-L1 expression cutoffs: PD-L1 high (if &gt;1% of the tumor area contained tumor-associated immune cells, ≥25% of tumor cells or ≥25% of immune cells stained for PD-L1; if ≤1% of the tumor area contained immune cells, ≥25% of tumor cells or 100% of immune cells stained for PD-L1) and PD-L1 low/negative (did not meet criteria for PD-L1 high). Results.— The assay met all predefined acceptance criteria for sensitivity, specificity, and precision. Interreader and intrareader precision overall agreement were 93.0% and 92.4%, respectively. For intraday reproducibility and interday precision, overall agreement was 99.2% and 100%, respectively. Interlaboratory overall agreement was 92.6%. In study CD-ON-MEDI4736-1108, durvalumab demonstrated clinical activity and durable responses in both PD-L1–high and PD-L1–low/negative subgroups, although objective response rates tended to be higher in the PD-L1–high subgroup than in the PD-L1–low/negative subgroup. Conclusions.— Determination of PD-L1 expression in urothelial carcinoma patients using the Ventana PD-L1 (SP263) assay was precise, highly reproducible, and clinically relevant.

Programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) expression in bladder cancer (BC): Differences in recurrent, progressive, and metastatic disease.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16001-e16001
Author(s):  
Axel Hegele ◽  
Franziska Wahl ◽  
Peter Rexin ◽  
W Nimphius ◽  
Rainer Hofmann ◽  
...  
Keyword(s):  
Immune Cells ◽  
Tumor Tissue ◽  
Staining Intensity ◽  
Time Interval ◽  
Recurrent Tumor ◽  
Instillation Therapy ◽  
Programmed Death ◽  
Muscle Invasive ◽  
Cell Death Protein

e16001 Background: The significance of PD-L1/PD-1 expression in BC is still unclear. In the present study we evaluated the PD-L1/PD-1 expression in tumor tissue (TT) and immune cells (IC) in the primary BC tumor as well as in case of BC recurrence and/or metastasis to detect possible changes in PD-L1/PD-1 expression using immunohistochemstry. Methods: PD-L1/PD-1 expression was determined in histological specimens of 20 pat. with a recurrent non-muscle invasive BC (NMIBC – Cohort 1) as well as in 20 pat. with muscle-invasive BC (MIBC- Cohort 2) treated by radical cystectomy and appearance of metastases during follow up using commercial available assays (E1L3N, Cell Signaling/ Zytomed). Staining intensity was performed using the Cologne Score. PD-L1/PD-1 status was compared between primary tumor and metastatic/recurrent/progressive BC tissue and correlated with clinical data. Results: Cohort 1: In NMIBC (18m,2f) a recurrent tumor occurred after 25 mo (1-114). In the recurrent TT PD-L1 expression was higher compared to primary BC in 15%. In case of progression higher PD-L1 expression was detectable in 42.9%. IC showed higher PD-L1 expression in 50% of recurrent NMIBC and in 42% in case of progression. PD-1 expression on IC rose in 70% in recurrent and 71% in progressive NMIBC without correlation to time interval of appearance. Cohort 2: After curative cystectomy (17m,3f) metastases occurred after a median time of 20.5 mo (0-58). Comparing PD-L1 expression in cystectomy specimens and metastases we found differences in 52.9% (4x down/5x up). Expression of PD-L1 in primary BC tissue correlated significantly with the time to metastasis (p < 0.05). Conclusions: In case of metastasis after cystectomy as well as in recurrent/progressive NMIBC we found distinct variations in PD-L1/PD-1 expression in TT and IC. In MIBC primary PD-L1 status correlates with the time to metastasis. Whether PD-L1/PD-1 status can be helpful for clinical decisions (i.e. adjuvant therapy, instillation therapy) or as prognosticator have to be subject of further study.

scholarly journals Optimal Evaluation of Programmed Death Ligand-1 on Tumor Cells Versus Immune Cells Requires Different Detection Methods

2018 ◽  
Vol 142 (8) ◽  
pp. 982-991 ◽  
Author(s):  
Kelly A. Schats ◽  
Emily A. Van Vré ◽  
Carolien Boeckx ◽  
Martine De Bie ◽  
Dorien M. Schrijvers ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Detection Method ◽  
Death Receptor ◽  
Detection Methods ◽  
Programmed Death Ligand 1 ◽  
Cell Staining ◽  
Programmed Death

Context.— The benefit of programmed death ligand-1 (PD-L1) immunohistochemistry (IHC) as a method to select patients who may benefit from programmed death receptor-1 (PD-1)/PD-L1 immunotherapies remains uncertain in many tumor indications. Objectives.— To compare the commercially available, approved PD-L1 IHC assays (22C3, 28-8, SP142, SP263), specifically identifying the changes in staining output created by altering the detection method. Design.— This pilot study investigates the respective PD-L1 kit assay staining patterns and related scoring of tumor cells and immune cells on lung carcinoma and melanoma. Furthermore, the influence of the detection method (platform and related reagents) on PD-L1 antibody performance is studied. Results.— The SP142 kit reveals more immune cell staining but less tumor cell staining than the other PD-L1 kits. Alternatively, the 22C3 and 28-8 kits show good tumor cell sensitivity, but less pronounced immune cell staining, even in tonsil. Tumor cell staining by the SP263 kit is comparable to that of 22C3 and 28-8 kits, while immune cell staining is better. Strikingly, the selection of the detection method has a major impact on the sensitivity of the assay for PD-L1 detection per cell type. Switching the detection method of the kits could largely circumvent the observed staining differences. Conclusions.— The diverse sensitivities caused by the choice of the detection method should be taken into consideration when selecting PD-L1 kits or developing PD-L1 IHC laboratory-developed tests. When using alternative kits or laboratory-developed tests, it is strongly recommended to reestablish their clinical utility per therapeutic agent or compare them with the original kit.

scholarly journals The Mechanisms Leading to Distinct Responses to PD-1/PD-L1 Blockades in Colorectal Cancers With Different MSI Statuses

2021 ◽  
Vol 11 ◽  
Author(s):  
Guanglin Cui
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Immune Cell ◽  
Basic Research ◽  
Final Analysis ◽  
Therapeutic Outcomes ◽  
Mutation Burden ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Cell Densities

Current clinical studies showed distinct therapeutic outcomes, in which CRC patients with mismatch repair-deficient (dMMR)/microsatellite instability high (MSI-H) seem to be relatively more “sensitive” in response to anti-programmed death-1 receptor (PD-1)/programmed death-1 receptor ligand 1 (PD-L1) therapy than those with mismatch repair-proficient (pMMR)/microsatellite instability-low (MSI-L). The mechanisms by which the same PD-1/PD-L1 blockades lead to two distinct therapeutic responses in CRC patients with different MSI statuses remain poorly understood and become a topic of great interest in both basic research and clinical practice. In this review of the potential mechanisms for the distinct response to PD-1/PD-L1 blockades between dMMR/MSI-H CRCs and pMMR/MSI-L CRCs, relevant references were electronically searched and collected from databases PubMed, MEDLINE, and Google scholar. Sixty-eight articles with full text and 10 articles by reference-cross search were included for final analysis after eligibility selection according to the guidelines of PRISMA. Analysis revealed that multiple factors e.g. tumor mutation burden, immune cell densities and types in the tumor microenvironment, expression levels of PD-1/PD-L1 and cytokines are potential determinants of such distinct response to PD-1/PD-L1 blockades in CRC patients with different MSI statuses which might help clinicians to select candidates for anti-PD-1/PD-L1 therapy and improve therapeutic response in patients with CRC.

scholarly journals PD-L1 (SP142) testing is concordant between Benchmark Ultra and Bond-III stainers

2021 ◽  
Author(s):  
Eva Compérat ◽  
André Oszwald ◽  
Gabriel Wasinger ◽  
Justine Wacquet ◽  
Morgan Rouprêt ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Cell ◽  
Immune Cell ◽  
Invasive Disease ◽  
Serial Sections ◽  
Programmed Death Ligand 1 ◽  
Non Invasive ◽  
Metastatic Bladder Cancer ◽  
Programmed Death ◽  
Immune Cell Score

Abstract Background Atezolizumab is an inhibitor of programmed death-ligand 1 (PD-L1), used to treat advanced or metastatic bladder cancer, and in trials for non-invasive disease. In order to be eligible for treatment, patients require a PD-L1 immune cell score ≥ 5%, using the Ventana SP142 PD-L1 assay. Many laboratories do not have access to the required Ventana Benchmark Ultra stainer, and it is unclear if the assay performs similarly on other stainers. In this study, we compare SP142 assay results between Ventana Benchmark Ultra and Leica Bond-III stainers. Methods Serial sections of 90 samples of transurethral bladder resections (comprising 51 pTaHG, 8 pTis, 18 pT1, 10 pT2 tumors) were stained using the SP142 PD-L1 antibody on Ventana Benchmark Ultra and Leica Bond-III stainers, manually scored, and compared using accuracy and Cohen’s kappa measures. Results Both devices yielded highly concordant PD-L1 immune cell scores (accuracy 0.84, Cohen’s κ 0.732). Moreover, we found similar tumor cell (TC) PD-L1 scores using both stainers, and a trend towards greater TC scores in pT2 stage samples (p = 0.05). Conclusion This study is the first to compare the SP142 antibody in bladder cancer on two different stainers. Our results indicate that both Benchmark Ultra and Bond-III stainers yield highly concordant results using the SP142 PD-L1 antibody.

scholarly journals Profiles of Peripheral Immune Cells of Uncomplicated COVID-19 Cases with Distinct Viral RNA Shedding Periods

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 514
Author(s):  
Denise Utami Putri ◽  
Cheng-Hui Wang ◽  
Po-Chun Tseng ◽  
Wen-Sen Lee ◽  
Fu-Lun Chen ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Severe Disease ◽  
Viral Rna ◽  
Disease Course ◽  
Peripheral Blood Mononuclear ◽  
Peripheral Immune Cells ◽  
Cell Profile

The heterogeneity of immune response to COVID-19 has been reported to correlate with disease severity and prognosis. While so, how the immune response progress along the period of viral RNA-shedding (VRS), which determines the infectiousness of disease, is yet to be elucidated. We aim to exhaustively evaluate the peripheral immune cells to expose the interplay of the immune system in uncomplicated COVID-19 cases with different VRS periods and dynamic changes of the immune cell profile in the prolonged cases. We prospectively recruited four uncomplicated COVID-19 patients and four healthy controls (HCs) and evaluated the immune cell profile throughout the disease course. Peripheral blood mononuclear cells (PBMCs) were collected and submitted to a multi-panel flowcytometric assay. CD19+-B cells were upregulated, while CD4, CD8, and NK cells were downregulated in prolonged VRS patients. Additionally, the pro-inflammatory-Th1 population showed downregulation, followed by improvement along the disease course, while the immunoregulatory cells showed upregulation with subsequent decline. COVID-19 patients with longer VRS expressed an immune profile comparable to those with severe disease, although they remained clinically stable. Further studies of immune signature in a larger cohort are warranted.

scholarly journals Stromal hyaluronan accumulation is associated with low immune response and poor prognosis in pancreatic cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kyösti Tahkola ◽  
Maarit Ahtiainen ◽  
Jukka-Pekka Mecklin ◽  
Ilmo Kellokumpu ◽  
Johanna Laukkarinen ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cell ◽  
Geographical Area ◽  
Prognostic Significance ◽  
Staining Intensity ◽  
Ductal Adenocarcinoma ◽  
Poor Survival ◽  
Negative Prognostic Factor ◽  
High Level ◽  
Immune Cell Score

AbstractHyaluronan (HA) accumulation has been associated with poor survival in various cancers, but the mechanisms for this phenomenon are still unclear. The aim of this study was to investigate the prognostic significance of stromal HA accumulation and its association with host immune response in pancreatic ductal adenocarcinoma (PDAC). The study material consisted of 101 radically treated patients for PDAC from a single geographical area. HA staining was evaluated using a HA-specific probe, and the patterns of CD3, CD8, CD73 and PD-L1 expression were evaluated using immunohistochemistry. HA staining intensity of tumour stromal areas was assessed digitally using QuPath. CD3- and CD8-based immune cell score (ICS) was determined. High-level stromal HA expression was significantly associated with poor disease-specific survival (p = 0.037) and overall survival (p = 0.013) In multivariate analysis, high-level stromal HA expression was an independent negative prognostic factor together with histopathological grade, TNM stage, CD73 positivity in tumour cells and low ICS. Moreover, high-level stromal HA expression was associated with low ICS (p = 0.017). In conclusion, stromal HA accumulation is associated with poor survival and low immune response in PDAC.

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