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Xiang Song, Yan Zhang, Li Zhang, Wengang Song, Lixin Shi
Hypoxia-associated metabolic reprogramming modulates the biological functions of many immune and non-immune cells, and affects immune response types and intensities. Adenosine and indoleamine 2,3-dioxygenase (IDO) are known immunosuppressors, and adenosine is a hypoxia-associated product. We investigated the impact of hypoxia on IDO production in dendritic cells (DCs). We found that hypoxia (1% O2 ) enhances IDO production in DCs, and this increase was dependent on the adenosine A3 receptor (A3R), but not A2aR or A2bR...
February 20, 2018: Oncotarget
Kentaro Inamura
Immunohistochemistry is a widely available technique that is less challenging and can provide clinically meaningful results quickly and cost-efficiently in comparison with other techniques. In addition, immunohistochemistry allows for the evaluation of cellular localization of proteins in the context of tumor structure. In an era of precision medicine, pathologists are required to classify lung cancer into specific subtypes and assess biomarkers relevant to molecular-targeted therapies. This review summarizes the hot topics of immunohistochemistry in lung cancer, including (i) adenocarcinoma vs squamous cell carcinoma; (ii) neuroendocrine markers; (iii) ALK, ROS1, and EGFR; (iv) PD-L1 (CD274); (v) lung carcinoma vs malignant mesothelioma; and (vi) NUT carcinoma...
March 14, 2018: Cancers
Soo Jung Lee, Sun-Young Jun, In Hee Lee, Byung Woog Kang, Su Yeon Park, Hye Jin Kim, Jun Seok Park, Gyu-Seog Choi, Ghilsuk Yoon, Jong Gwang Kim
PURPOSE: This study attempted to reveal the prognostic impact of microsatellite instability-high (MSI-H) colon cancer with tumor-infiltrating immune cells (TIICs) and immune checkpoint protein expression, which are good candidates for immunotherapy. MATERIALS AND METHODS: The study included 89 patients with MSI-H colon cancer who underwent curative surgery at Kyungpook National University Chilgok Hospital. The expression status of specific inhibitory receptors, such as CD274 (programmed death-ligand 1, PD-L1), PDCD1 (programmed cell death 1, PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), and indolamine 2'3'-dioxygenase 1 (IDO1), was retrospectively analyzed using immunohistochemistry (IHC)...
March 8, 2018: Journal of Cancer Research and Clinical Oncology
Sathisha Upparahalli Venkateshaiah, Akanksha Mishra, Murli Manohar, Alok K Verma, Priya Rajavelu, Rituraj Niranjan, Laurianne G Wild, Nereida A Parada, Uwe Blecker, Joseph A Lasky, Anil Mishra
The current studies demonstrate a critical role of IL-18 in transforming IL-5 generated naïve eosinophils into the distinct inflammatory CD101+ CD274+ expressing mature and activated tissue eosinophils that promote disease pathogenesis.
February 27, 2018: Journal of Allergy and Clinical Immunology
Xiaoyan Liu, Jesse J Swen, Meta H M Diekstra, Epie Boven, Daniel Castellano, Hans Gelderblom, Ron Hj Mathijssen, Sita H Vermeulen, Egbert Oosterwijk, Kerstin Junker, Max Roessler, Kristin Alexiusdottir, Asgerdur Sverrisdottir, Marius T Radu, Valentin Ambert, Timothy Eisen, Anne Y Warren, Cristina Rodríguez-Antona, Jesus García-Donás, Karel K M Koudijs, Stefan Böhringer, Lambertus A Kiemeney, Brian Rini, Henk-Jan Guchelaar
PURPOSE: The survival of patients with clear cell metastatic renal cell carcinoma (cc-mRCC) has improved substantially since the introduction of tyrosine kinase inhibitors (TKIs). With the fact that TKIs interact with immune responses, we investigated whether polymorphisms of genes involved in immune checkpoints are related to the clinical outcome of cc-mRCC patients treated with sunitinib as first TKI. EXPERIMENTAL DESIGN: 27 single nucleotide polymorphisms (SNPs) in CD274 (PD-L1) , PDCD1 (PD-1) and CTLA-4 were tested for a possible association with progression-free survival (PFS) and overall survival (OS) in a discovery cohort of 550 sunitinib-treated cc-mRCC patients...
February 28, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Carmen D Herling, Nima Abedpour, Jonathan Weiss, Anna Schmitt, Ron Daniel Jachimowicz, Olaf Merkel, Maria Cartolano, Sebastian Oberbeck, Petra Mayer, Valeska Berg, Daniel Thomalla, Nadine Kutsch, Marius Stiefelhagen, Paula Cramer, Clemens-Martin Wendtner, Thorsten Persigehl, Andreas Saleh, Janine Altmüller, Peter Nürnberg, Christian Pallasch, Viktor Achter, Ulrich Lang, Barbara Eichhorst, Roberta Castiglione, Stephan C Schäfer, Reinhard Büttner, Karl-Anton Kreuzer, Hans Christian Reinhardt, Michael Hallek, Lukas P Frenzel, Martin Peifer
Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in BTG1 (2 patients) and homozygous deletions affecting CDKN2A/B (3 patients) that developed during treatment, as well as a mutation in BRAF and a high-level focal amplification of CD274 (PD-L1) that might pinpoint molecular aberrations offering structures for further therapeutic interventions...
February 20, 2018: Nature Communications
Arathi Jayaraman, Monica Sharma, Bellur Prabhakar, Mark Holterman, Sundararajan Jayaraman
We have recently demonstrated that treatment of NOD mice with the epigenetic drug Trichostatin A (TSA) ameliorated myelin peptide induced progressive experimental autoimmune encephalomyelitis (P-EAE). Protection was accompanied by induction of antigen-specific T-cell tolerance in the periphery and reduced the influx of T cells into the spinal cord. In this investigation, we examined whether the epigenetic drug could impact the innate immune system as well. Whereas the mature (MHC class II + ) CD11b + Ly-6G + neutrophils expanded substantially in the peripheral lymphoid compartment during the preclinical phase, the MHC class II + , CD11b + Ly-6C + mature monocytes increased modestly throughout the disease course...
February 14, 2018: Experimental Neurology
Anna Buermann, Stoyan Petkov, Björn Petersen, Rabea Hein, Andrea Lucas-Hahn, Wiebke Baars, Antje Brinkmann, Heiner Niemann, Reinhard Schwinzer
BACKGROUND: The programmed cell death-1 (PD-1, CD279)/PD-Ligand1 (PD-L1, CD274) receptor system is crucial for controlling the balance between immune activation and induction of tolerance via generation of inhibitory signals. Expression of PD-L1 is associated with reduced immunogenicity and renders cells and tissues to an immune-privileged/tolerogenic state. METHODS: To apply this concept for clinical xenotransplantation, we generated human (h)PD-L1 transgenic pigs and characterized expression and biological function of the transgene at the cellular level...
February 15, 2018: Xenotransplantation
Qi Lai, Haiyong Wang, Angui Li, Yinhui Xu, Liang Tang, Qiang Chen, Chunfang Zhang, Yang Gao, Jianfei Song, Zhenzong Du
IFN-γ-induced PD-L1 expression represents the existence of tumor-specific T cells, which predicts high-response rate to anti-PD-1/L1 therapy, but loss-of-function of IFN signals (e.g., JAK mutation) induces adaptive immune resistance in patients with low-response rate. Interferon regulatory factors (IRF) are frequently epigenetic silenced in carcinogenesis, while the role of methylation in anti-PD-1/L1 therapy remains unclear. We here investigated the methylation status of IFN-γ related genes IRF1/8 and IFN-α/β-related genes IRF3/7 in lung cancer tissues and found that only highly methylated IRF1 and 7 negatively correlated to cd274 (coding PD-L1) expression, similar to JAK mutation...
February 9, 2018: Oncogene
Alina Franzen, Timo J Vogt, Tim Müller, Jörn Dietrich, Andreas Schröck, Carsten Golletz, Peter Brossart, Friedrich Bootz, Jennifer Landsberg, Glen Kristiansen, Dimo Dietrich
Background: DNA methylation of the immune checkpoint gene PD-L1 has recently been shown to be associated with PD-L1 mRNA expression in various malignancies. This study aimed to investigate the association of PD-L1 and PD-L2 methylation with mRNA expression, immune cell infitration, protein expression and human papilloma virus (HPV) infection in head and neck squamous cell carcinoma (HNSCC) patients. Results: DNA methylation of PD-L1 and PD-L2 correlates inversely with mRNA expression ( PD-L1 : p ≤ 0...
January 2, 2018: Oncotarget
Melanie Boxberg, Katja Steiger, Ulrich Lenze, Hans Rechl, Rüdiger von Eisenhart-Rothe, Klaus Wörtler, Wilko Weichert, Rupert Langer, Katja Specht
Therapies targeting programmed death 1-(PD-1) or its ligand (PD-L1), promoting antitumor T-cell activity have been successfully introduced into clinical practice. Clinical response correlates with PD-L1 expression by tumor cells or immune cells within the tumor microenvironment. The PD-L1/PD-1 axis and tumor microenvironment has been rarely studied in high-grade sarcomas of soft tissue (hSTS), a group of rare, genetically heterogenous and clinically aggressive tumors. We examined PD-L1 protein and CD274/PD-L1 gene copy number variations in 128 primary resected, therapy-naive hSTS using immunohistochemistry and fluorescence-in-situ hybridization...
2018: Oncoimmunology
Margaretha G M Roemer, Robert A Redd, Fathima Zumla Cader, Christine J Pak, Sara Abdelrahman, Jing Ouyang, Stephanie Sasse, Anas Younes, Michelle Fanale, Armando Santoro, Pier Luigi Zinzani, John Timmerman, Graham P Collins, Radhakrishnan Ramchandren, Jonathon B Cohen, Jan Paul De Boer, John Kuruvilla, Kerry J Savage, Marek Trneny, Stephen Ansell, Kazunobu Kato, Benedetto Farsaci, Anne Sumbul, Philippe Armand, Donna S Neuberg, Geraldine S Pinkus, Azra H Ligon, Scott J Rodig, Margaret A Shipp
Purpose Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p24.1/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation. Programmed death 1 (PD-1) receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells. Herein, we assess bases of sensitivity to PD-1 blockade in patients with relapsed/refractory cHL who were treated with nivolumab (anti-PD-1) in the CheckMate 205 trial...
February 2, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Stefania Bellone, Natalia Buza, Jungmin Choi, Luca Zammataro, Laurie Gay, Julia A Elvin, David L Rimm, Yuting Liu, Elena Ratner, Peter E Schwartz, Alessandro D Santin
PURPOSE: Ovarian carcinoma no longer responsive to surgery and chemotherapy remains an incurable disease. Alternative therapeutic options remain desperately needed. EXPERIMENTAL DESIGN: We describe a heavily pretreated ovarian cancer patient with recurrent disease experiencing a remarkable clinical response to treatment with the anti-PD1 immune check-point inhibitor pembrolizumab. The clinical, pathological, and genomic characteristics of this exceptional ovarian cancer responder were carefully investigated using immunohistochemistry (IHC), quantitative multiplex fluorescence methods (ie, automated quantitative analysis, AQUA) and whole exome sequencing (WES) techniques...
January 19, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Willemijn Hobo, Tim J A Hutten, Nicolaas P M Schaap, Harry Dolstra
New immunotherapeutic interventions have revolutionized cancer treatment. The immune responsiveness of acute myeloid leukaemia (AML) was first demonstrated by allogeneic stem cell transplantation. In addition, milder immunotherapeutic approaches are exploited. However, the long-term efficacy of these therapies is hampered by various immune resistance and editing mechanisms. In this regard, co-inhibitory signalling pathways have been shown to play a crucial role. Via up-regulation of inhibitory checkpoints, tumour-reactive T cell and Natural Killer cell responses can be strongly impeded...
January 9, 2018: British Journal of Haematology
T Smith, L Engelbrecht, C Smith
Background: In vivo studies have shown grape seed-derived polyphenols (GSP) to benefit in recovery from muscle injury by modulation of neutrophil infiltration into damaged tissue, thereby reducing secondary damage, as well as by facilitating an early anti-inflammatory macrophage phenotype shift. The current study aimed to provide data in this context from human models and to elucidate specific molecular targets of GSP.Using a placebo-controlled, double-blind study design, eighteen normally healthy volunteers between the ages of 18-35 years old (13 female and 5 male) were orally supplemented with 140 mg/day of GSP for 2 weeks...
2018: Journal of Inflammation
David D W Twa, Anja Mottok, Kerry J Savage, Christian Steidl
Primary testicular lymphomas (PTL) are the most prevalent type of testicular cancer arising in men over the age of 60. PTL accounts for approximately 1-2% of all non-Hodgkin lymphomas and most present with localized disease but despite this, outcome is poor. The majority of cases represent an extranodal manifestation of diffuse large B-cell lymphoma (DLBCL), known as primary testicular DLBCL (PT-DLBCL). Gene expression profiling has established that over 75% of PT-DLBCLs resemble the activated B-cell-like (ABC) or non-germinal center subtype of nodal DLBCL...
December 20, 2017: Blood Reviews
Paolo Bossi, Marco Siano, Cristiana Bergamini, Maria Cossu Rocca, Andrea P Sponghini, Marco Giannoccaro, Luca Tonella, Alessandro Paoli, Edoardo Marchesi, Federica Perrone, Silvana Pilotti, Laura D Locati, Silvana Canevari, Lisa Licitra, Loris De Cecco
Prediction of benefit from combined chemotherapy and the antiepidermal growth factor receptor cetuximab is a not yet solved question in head and neck squamous cell carcinoma (HNSCC). In a selected series of 14 long progression-free survival (PFS) and 26 short PFS patients by whole gene and microRNA expression analysis, we developed a model potentially predictive of cetuximab sensitivity. To better decipher the "omics" profile of our patients, we detected transcript fusions by RNA-seq through a Pan-Cancer panel targeting 1385 cancer genes...
2017: Disease Markers
Mehdi Najar, Hussein Fayyad-Kazan, Wissam H Faour, Adil El Taghdouini, Gordana Raicevic, Leo A van Grunsven, Mustapha Najimi, Etienne Sokal, Laurence Lagneaux
Human hepatic stellate cells (HSCs) demonstrated great immunological plasticity with important consequences for liver cell therapy. Activated HSCs (aHSCs) are in vitro reverted (rHSCs) to a quiescent-like phenotype with potential benefit to reduce liver fibrosis. The goal of this study is to establish and compare the immunological profile of activated and in vitro reverted HSCs and to investigate the impact of inflammatory priming on the immunobiology of both HSCs populations. The distribution of inflammatory primed activated and reverted HSCs across the different phases of the cell cycle is assessed by flow cytometry...
December 12, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
W Robert Liu, Margaret A Shipp
Classical Hodgkin lymphoma (cHL) is an unusual B-cell-derived malignancy in which rare malignant Hodgkin and Reed-Sternberg (HRS) cells are surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. This striking feature suggests that malignant HRS cells escape immunosurveillance and interact with immune cells in the cancer microenvironment for survival and growth. We previously found that cHLs have a genetic basis for immune evasion: near-uniform copy number alterations of chromosome 9p24...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
Mariona Cabo, Rienk Offringa, Laurence Zitvogel, Guido Kroemer, Aura Muntasell, Lorenzo Galluzzi
The goal of cancer immunotherapy is to establish new or boost pre-existing anticancer immune responses that eradicate malignant cells while generating immunological memory to prevent disease relapse. Over the past few years, immunomodulatory monoclonal antibodies (mAbs) that block co-inhibitory receptors on immune effectors cells - such as cytotoxic T lymphocyte-associated protein 4 (CTLA4), programmed cell death 1 (PDCD1, best known as PD-1) - or their ligands - such as CD274 (best known as PD-L1) - have proven very successful in this sense...
2017: Oncoimmunology
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