scholarly journals Validated programmed cell death ligand 1 immunohistochemistry assays (E1L3N and SP142) reveal similar immune cell staining patterns in melanoma when using the same sensitive detection system

2016 ◽  
Vol 70 (2) ◽  
pp. 253-263 ◽  
Author(s):  
Kelly A Schats ◽  
Emily A Van Vré ◽  
Stefanie De Schepper ◽  
Carolien Boeckx ◽  
Dorien M Schrijvers ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Cell ◽  
Detection System ◽  
Sensitive Detection ◽  
Cell Staining

scholarly journals Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in Melanoma

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 450 ◽  
Author(s):  
Saeed Daneshmandi ◽  
Barbara Wegiel ◽  
Pankaj Seth
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Lactate Dehydrogenase ◽  
Programmed Cell Death ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Treg Cells ◽  
Interferon Γ ◽  
Mitochondrial Activity ◽  
Small Subset

Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients. We have recently reported that programmed cell death protein-1 (PD-1) ligand (PD-L1) expression is regulated by lactate present at high levels in the tumor microenvironment (TME). We hypothesized that the efficacy of anti-PD-1 treatment can be improved by blocking the lactate-generating enzyme, lactate dehydrogenase-A (LDH-A). Anti-PD-1 treatment of mice harboring LDH-A deficient B16-F10 melanoma tumors led to an increase in anti-tumor immune responses compared to mice implanted with tumors expressing LDH-A. Specifically, we observed heightened infiltration of natural killer (NK) cells and CD8+ cytotoxic T cells in the LDH-A deficient tumors. These infiltrated cytotoxic cells had an elevated production of interferon-γ (IFN-γ) and granzyme B. Mechanistically, CD8+ T cells isolated from the TME of LDH-A deficient B16-F10 melanoma tumors and treated with anti-PD-1 showed enhanced mitochondrial activity and increased reactive oxygen species (ROS) levels. Moreover, infiltration of T regulatory (Treg) cells was diminished in LDH-A deficient tumors treated with anti-PD-1. These altered immune cell profiles were clinically relevant as they were accompanied by significantly reduced tumor growth. Our study suggests that blocking LDH-A in the tumor might improve the efficacy of anti-PD-1 therapy.

scholarly journals Unveiling the immune infiltrate modulation in cancer and response to immunotherapy by MIXTURE—an enhanced deconvolution method

2020 ◽  
Author(s):  
Elmer A Fernández ◽  
Yamil D Mahmoud ◽  
Florencia Veigas ◽  
Darío Rocha ◽  
Matías Miranda ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Cells ◽  
Immune Cell ◽  
Immune Escape ◽  
Intratumor Heterogeneity ◽  
Support Vector ◽  
Tumor Immune Escape ◽  
Immune Infiltrate ◽  
Tumor Biopsies

Abstract The accurate quantification of tumor-infiltrating immune cells turns crucial to uncover their role in tumor immune escape, to determine patient prognosis and to predict response to immune checkpoint blockade. Current state-of-the-art methods that quantify immune cells from tumor biopsies using gene expression data apply computational deconvolution methods that present multicollinearity and estimation errors resulting in the overestimation or underestimation of the diversity of infiltrating immune cells and their quantity. To overcome such limitations, we developed MIXTURE, a new ν-support vector regression-based noise constrained recursive feature selection algorithm based on validated immune cell molecular signatures. MIXTURE provides increased robustness to cell type identification and proportion estimation, outperforms the current methods, and is available to the wider scientific community. We applied MIXTURE to transcriptomic data from tumor biopsies and found relevant novel associations between the components of the immune infiltrate and molecular subtypes, tumor driver biomarkers, tumor mutational burden, microsatellite instability, intratumor heterogeneity, cytolytic score, programmed cell death ligand 1 expression, patients’ survival and response to anti-cytotoxic T-lymphocyte-associated antigen 4 and anti-programmed cell death protein 1 immunotherapy.

Programmed Cell Death 1 (PD-1) Ligand (PD-L1) Expression in Solid Tumors As a Predictive Biomarker of Benefit From PD-1/PD-L1 Axis Inhibitors: A Systematic Review and Meta-Analysis

2017 ◽  
pp. 1-15 ◽  
Author(s):  
Monica Khunger ◽  
Adrian V. Hernandez ◽  
Vinay Pasupuleti ◽  
Sagar Rakshit ◽  
Nathan A. Pennell ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Solid Tumors ◽  
Immune Cell ◽  
Meta Analysis ◽  
Objective Response ◽  
Small Cell Lung ◽  
Programmed Cell Death 1 ◽  
Tumor Types

Purpose Drugs targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway show significant clinical activity across several tumor types. However, a majority of patients do not respond to these agents. Use of biomarker assays to predict response to these agents is an active area of research; however, the predictive value of PD-L1 immunohistochemistry (IHC) assays is largely inconsistent across clinical trials. In this meta-analysis of clinical trials of PD-1/PD-L1–targeted agents, we evaluate the predictive value of a tumor and tumor-infiltrating immune cell PD-L1 IHC assay as a biomarker for objective response to PD-1/PD-L1 inhibitors. Methods We searched databases (PubMed, Medline, ASCO abstracts, European Society for Medical Oncology abstracts, and Scopus) up until December 2016 for clinical trials using PD-1/PD-L1 inhibitors with reported PD-L1 biomarker data. Objective response rates (primary end point) from all phase I to III trials investigating nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab in advanced solid tumors were collected. Odds ratios (ORs) for response in PD-L1–positive patients compared with PD-L1–negative patients were calculated using the DerSimonian-Laird random effects model to combine trials. We performed meta-analysis as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results Forty-one distinct trials with 6,664 patients were identified. PD-L1 expression was predictive of favorable response across all tumor types (OR, 2.26; 95% CI, 1.85 to 2.75; P < .001), with the significantly largest effect observed in non–small-cell lung cancer (OR, 2.51; 95% CI, 1.99 to 3.17; P < .001). A subgroup analysis across all non–small-cell lung cancer trials using nivolumab and Dako clone 28-8 (Dako, Carpinteria, CA) IHC antibody assay yielded a significantly higher objective response rate in patients with tumor PD-L1 expression even at the minimum cutoff value of 1% (OR, 2.17; 95% CI, 1.03 to 4.57). Conclusion Our meta-analysis shows that tumor and tumor-infiltrating immune cell PD-L1 overexpression based on IHC is associated with significantly higher response rates to PD-1/PD-L1 axis inhibitors across a range of malignant solid tumors.

scholarly journals Immune-Checkpoint Blockade Therapy in Lymphoma

2020 ◽  
Vol 21 (15) ◽  
pp. 5456 ◽  
Author(s):  
Ayumi Kuzume ◽  
SungGi Chi ◽  
Nobuhiko Yamauchi ◽  
Yosuke Minami
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Malignant Lymphoma ◽  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Host Immune System ◽  
Cell Death Protein

Tumor cells use immune-checkpoint pathways to evade the host immune system and suppress immune cell function. These cells express programmed cell-death protein 1 ligand 1 (PD-L1)/PD-L2, which bind to the programmed cell-death protein 1 (PD-1) present on cytotoxic T cells, trigger inhibitory signaling, and reduce cytotoxicity and T-cell exhaustion. Immune-checkpoint blockade can inhibit this signal and may serve as an effective therapeutic strategy in patients with solid tumors. Several trials have been conducted on immune-checkpoint inhibitor therapy in patients with malignant lymphoma and their efficacy has been reported. For example, in Hodgkin lymphoma, immune-checkpoint blockade has resulted in response rates of 65% to 75%. However, in non-Hodgkin lymphoma, the response rate to immune-checkpoint blockade was lower. In this review, we evaluate the biology of immune-checkpoint inhibition and the current data on its efficacy in malignant lymphoma, and identify the cases in which the treatment was more effective.

Versinia pestis YopJ, YopT, and YopK coordinate programmed cell death and cytokine responses to promote pneumonic plague

2017 ◽  
Author(s):  
◽  
Rachel M. Olson
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Bacterial Growth ◽  
Cell Function ◽  
Immune Cell ◽  
Effector Proteins ◽  
University Of Missouri ◽  
Cellular Machinery ◽  
The University ◽  
Inflammatory Macrophages

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Yersinia pestis has been responsible for three major pandemics of plague, including the infamous Black Death that killed 250 million people in Europe. The disease progresses rapidly due to a combination of bacterial growth and host immunopathology. During infection, Y. pestis utilizes a type III secretion system (T3SS), which is essential for virulence, to inject effector proteins that disrupt immune cell function. The majority of the Yops are dedicated to the control of programmed cell death of immune cells, namely macrophages and neutrophils, and through this, it has been proposed that initially there is immune suppression followed by an acute inflammatory response that accelerates bacterial growth and disease. Recent work has focused on the inflammasome, cellular machinery that is activated upon insertion of the translocation pore that results in host cell lysis and the release of inflammatory cytokines. In this work, we defined a novel pathogenesis mechanism involving the activation of rapid lysis of inflammatory macrophages via necroptosis by injected bacterial effectors YopT and YopJ, each with cysteine protease activity. We show that YopT is a virulence factor for plague, while deletion of YopJ had no detectable impact on virulence. Further, we found that injection of catalytically inactive YopJ induces strong activation of the inflammasome and stimulates host defense against plague. YopK modulates the effects of YopT and YopJ. Overall, it appears that induction of necroptosis by YopT and YopJ subverts the activation of the inflammasome and contributes to pathogenesis of plague.

scholarly journals Burn the house, save the day: pyroptosis in pathogen restriction

Inflammasome ◽  
2016 ◽  
Vol 2 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Dave Boucher ◽  
Kaiwen W. Chen ◽  
Kate Schroder
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Cell ◽  
Innate Immune ◽  
Cytokine Storm ◽  
Cell Death Pathways ◽  
Multicellular Organisms ◽  
Pathogen Clearance ◽  
Inflammatory Caspases

AbstractMany programmed cell death pathways are essential for organogenesis, development, immunity and the maintenance of homeostasis in multicellular organisms. Pyroptosis, a highly proinflammatory form of cell death, is a critical innate immune response to prevent intracellular infection. Pyroptosis is induced upon the activation of proinflammatory caspases within macromolecular signalling platforms called inflammasomes. This article reviews our understanding of pyroptosis induction, the function of inflammatory caspases in pyroptosis execution, and the importance of pyroptosis for pathogen clearance. It also highlights the situations in which extensive pyroptosis may in fact be detrimental to the host, leading to immune cell depletion or cytokine storm. Current efforts to understand the beneficial and pathological roles of pyroptosis bring the promise of new approaches to fight infectious diseases.

Anti-VEGF/VEGFR2 Monoclonal Antibodies and their Combinations with PD-1/PD-L1 Inhibitors in Clinic

2020 ◽  
Vol 20 (1) ◽  
pp. 3-18 ◽  
Author(s):  
Feng Gao ◽  
Chun Yang
Keyword(s):  
Cell Death ◽  
Monoclonal Antibodies ◽  
Programmed Cell Death ◽  
Clinical Studies ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Suppressor Cells ◽  
Vegf Receptor ◽  
Anti Vegf ◽  
Vegfr2 Signaling

The vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway is one of the most important pathways responsible for tumor angiogenesis. Currently, two monoclonal antibodies, anti-VEGF-A antibody Bevacizumab and anti-VEGFR2 antibody Ramucizumab, have been approved for the treatment of solid tumors. At the same time, VEGF/VEGFR2 signaling is involved in the regulation of immune responses. It is reported that the inhibition of this pathway has the capability to promote vascular normalization, increase the intra-tumor infiltration of lymphocytes, and decrease the number and function of inhibitory immune cell phenotypes, including Myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and M2 macrophages. On this basis, a number of clinical studies have been performed to investigate the therapeutic potential of VEGF/VEGFR2-targeting antibodies plus programmed cell death protein 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) inhibitors in various solid tumor types. In this context, VEGF/VEGFR2- targeting antibodies, Bevacizumab and Ramucizumab are briefly introduced, with a description of the differences between them, and the clinical studies involved in the combination of Bevacizumab/ Ramucizumab and PD-1/PD-L1 inhibitors are summarized. We hope this review article will provide some valuable clues for further clinical studies and usages.

scholarly journals Primary Cutaneous Extranodal NK/T-Cell Lymphoma, Nasal Type, with Extensive Skin Lesions: A Case Report with Immune Cell Shift

2020 ◽  
Author(s):  
Xie Hongjian ◽  
Shi Yujie ◽  
Kong Lingfei
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Immune Cell ◽  
Cell Lymphoma ◽  
Skin Lesions ◽  
T Cell Lymphoma ◽  
Nasal Type ◽  
Localized Disease ◽  
Nk T Cell

Abstract Background: Primary cutaneous extranodal natural killer (NK)/T-cell lymphoma, nasal type (PC-ENKTL), is a rare entity of malignancies of NK cells or cytotoxic T cells, characterized by an association with Epstein-Barr virus (EBV) infection. Despite its aggressive behavior, PC-ENKTL is mostly found as a localized disease. Data regarding PC-ENKTL with generalized skin lesions have only rarely been characterized in clinical studies so far. Case presentation: We present a case of PC-ENKTL, nasal type, in a 38-year–old female with a history of disseminated cutaneous plaques, ulcers and painful nodules that originated in her right leg skin as a small raised papule and expanded quickly over the entire body, ranging in diameter from 1 cm to 6 cm. The patient did not show any involvement of other sites except skin. Histologic, immunophenotypic, genetic and clinical features consistent with the diagnosis of primary cutaneous NK/T-cell lymphoma, nasal type. The status of immune cells was analyzed using a panel of monoclonal antibodies and revealed negative stain for CD163, CD68, programmed cell death (PD-1)/programmed cell death l ligand 1(PD-L1), and FoxP3. Chemotherapy followed by radiotherapy was planned but the patient was experienced disease progression and died at 3 months as a result of lymphoma.Conclusions: In contrast to NK/T-cell lymphoma with localized disease, PC-ENKTL with generalized skin lesions tend to be more aggressive, with short survival and extremely poor response to therapy. We propose that the immune cell shift may be related to the severity of the patient.

scholarly journals Association of Galectin 9 Expression with Immune Cell Infiltration, Programmed Cell Death Ligand-1 Expression, and Patient’s Clinical Outcome in Triple-Negative Breast Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1383
Author(s):  
Mi-Ha Ju ◽  
Kyung-Do Byun ◽  
Eun-Hwa Park ◽  
Jin-Hwa Lee ◽  
Song-Hee Han
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Clinical Outcome ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration

Galectin-9 (Gal-9) is an immune checkpoint protein that facilitates T cell exhaustion and modulates the tumor-associated microenvironment, and could be a potential target for immune checkpoint inhibition. This study was conducted to assess Gal-9 expression in triple-negative breast cancer (TNBC) and evaluate its association with programmed cell death ligand 1 (PD-L1) expression and immune cell infiltration in tumors and the clinical outcome of patients. Overall, 109 patients with TNBC were included. Gal-9 expression was assessed its relationships with tumor clinicopathologic characteristics, tumor-infiltrating lymphocyte (TIL) levels, PD-L1+ immune cells, and tumor cells by tissue microarray and immunohistochemistry. Low Gal-9 expression was statistically correlated with higher tumor stage (p = 0.031) and presence of lymphovascular invasion (p = 0.008). High Gal-9 expression was associated with a high level of stromal TILs (sTIL; p = 0.011) and positive PD-L1 expression on tumor cells (p = 0.004). In survival analyses, low Gal-9 expression was associated with significantly poor OS (p = 0.013) in patients with TNBC with PD-L1 negativity in tumor cells. Our findings suggest that increased Gal-9 expression is associated with changes in the antitumor microenvironment, such as increased immune cell infiltration and antimetastatic changes. This study emphasizes the predictive value and promising clinical applications of Gal-9 in TNBC.

Sign in / Sign up

Export Citation Format

Share Document