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https://www.readbyqxmd.com/read/29036980/-cd137-induces-vascular-muscle-cells-phenotype-transformation-through-activating-nuclear-factor-of-activated-t-cells-1-signaling
#1
W Zhong, B Li, J Liu, Y Xu, R Chen, C Shao, Z Q Wang, J C Yan
Objective: To investigate whether CD137 induces primary vascular muscle cells (VSMCs) phenotype transformation through activating nuclear factor of activated T-cells 1(NFATc1) signaling. Methods: VSMCs were obtained from aorta of C57BL/6J mice (8 weeks, male) through tissue-piece inoculating. Cells were divided into control group, CD137 agonist group (treated with CD137L recombinant protein) and anti-CD137 group (treated with anti-CD137 antibody). In si-RNA transfection assay, cells were divided into si-control group and si-NFATc1 group which were transfected with control or si-NFATc1 sequence respectively...
September 24, 2017: Zhonghua Xin Xue Guan Bing za Zhi
https://www.readbyqxmd.com/read/28955345/protective-cytomegalovirus-cmv-specific-t-cell-immunity-is-frequent-in-kidney-transplant-patients-without-serum-anti-cmv-antibodies
#2
Nicolle H R Litjens, Ling Huang, Burç Dedeoglu, Ruud W J Meijers, Jaap Kwekkeboom, Michiel G H Betjes
The absence of anti-cytomegalovirus (CMV) immunoglobulin G (IgG) is used to classify pretransplant patients as naïve for CMV infection (CMV(neg) patients). This study assessed whether pretransplant CMV-specific T-cell immunity exists in CMV(neg) patients and whether it protects against CMV infection after kidney transplantation. The results show that CMV-specific CD137(+)IFNγ(+)CD4(+) and CD137(+)IFNγ(+)CD8(+) memory T cells were present in 46 and 39% of CMV(neg) patients (n = 28) although at much lower frequencies compared to CMV(pos) patients (median 0...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28945841/antigen-cross-presentation-and-t-cell-cross-priming-in-cancer-immunology-and-immunotherapy
#3
Alfonso R Sánchez-Paulete, Álvaro Teijeira, Francisco J Cueto, Saray Garasa, José L Pérez-Gracia, Álvaro Sánchez-Arráez, David Sancho, Ignacio Melero
Dendritic cells are the main professional antigen-presenting cells for induction of T cell adaptive responses. Cancer cells express tumor antigens, including neoantigens generated by non-synonymous mutations, but are poor for antigen presentation and for providing costimulatory signals for T-cell priming. Mounting evidence suggests that antigen transfer to dendritic cells (DCs) and their surrogate presentation on MHC class I and II molecules together with costimulatory signals is paramount for induction of viral and cancer immunity...
September 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28928380/predictors-of-responses-to-immune-checkpoint-blockade-in-advanced-melanoma
#4
N Jacquelot, M P Roberti, D P Enot, S Rusakiewicz, N Ternès, S Jegou, D M Woods, A L Sodré, M Hansen, Y Meirow, M Sade-Feldman, A Burra, S S Kwek, C Flament, M Messaoudene, C P M Duong, L Chen, B S Kwon, A C Anderson, V K Kuchroo, B Weide, F Aubin, C Borg, S Dalle, O Beatrix, M Ayyoub, B Balme, G Tomasic, A M Di Giacomo, M Maio, D Schadendorf, I Melero, B Dréno, A Khammari, R Dummer, M Levesque, Y Koguchi, L Fong, M Lotem, M Baniyash, H Schmidt, I M Svane, G Kroemer, A Marabelle, S Michiels, A Cavalcanti, M J Smyth, J S Weber, A M Eggermont, L Zitvogel
Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28923858/anti-cd137-suppresses-tumor-growth-by-blocking-reverse-signaling-by-cd137-ligand
#5
Sang W Kang, Sang Chul Lee, So H Park, Juyang Kim, Hyeon H Kim, Hyeon-Woo Lee, Su-Kil Seo, Byoung S Kwon, Hong R Cho, Byungsuk Kwon
CD137 (4-1BB) is a T cell co-stimulatory molecule and agonstic CD137 antibodies are currently being evaluated in clinic as cancer immunotherapy. Recently, it was found that CD137-/- mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here we report findings related to reverse signaling by CD137 ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results...
September 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28905118/administration-of-low-dose-combination-anti-ctla4-anti-cd137-and-anti-ox40-into-murine-tumor-or-proximal-to-the-tumor-draining-lymph-node-induces-systemic-tumor-regression
#6
Jonathan P O Hebb, Adriane R Mosley, Felipe Vences-Catalán, Narendiran Rajasekaran, Anna Rosén, Peter Ellmark, Dean W Felsher
The delivery of immunomodulators directly into the tumor potentially harnesses the existing antigen, tumor-specific infiltrating lymphocytes, and antigen presenting cells. This can confer specificity and generate a potent systemic anti-tumor immune response with lower doses and less toxicity compared to systemic administration, in effect an in situ vaccine. Here, we test this concept using the novel combination of immunomodulators anti-CTLA4, -CD137, and -OX40. The triple combination administered intratumorally at low doses to one tumor of a dual tumor mouse model had dramatic local and systemic anti-tumor efficacy in lymphoma (A20) and solid tumor (MC38) models, consistent with an abscopal effect...
September 13, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28875845/new-trends-in-anti-cancer-therapy-combining-conventional-chemotherapeutics-with-novel-immunomodulators
#7
Amy L Wilson, Magdalena Plebanski, Andrew N Stephens
Cancer is one of the leading causes of death worldwide, and current research has focused on the discovery of novel approaches to effectively treat this disease. Recently, a considerable number of clinical trials have demonstrated the success of immunomodulatory therapies for the treatment of cancer. Monoclonal antibodies can target components of the immune system to either i) agonise co-stimulatory molecules, such as CD137, OX40 and CD40; or ii) inhibit immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its corresponding ligand PD-L1...
August 29, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28858434/cd4-cd28-null-t-cells-are-not-alloreactive-unless-stimulated-by-interleukin-15
#8
B Dedeoglu, N H R Litjens, M Klepper, R Kraaijeveld, W Verschoor, C C Baan, M G H Betjes
Proinflammatory, cytotoxic CD4(+) CD28(null) T cells can be substantially expanded in patients with end-stage renal disease. These cells have been associated with the risk for rejection, but their alloreactive potential is unknown. CD4(+) CD28(null) T cells were stimulated with HLA-mismatched antigen presenting cells in the absence/presence of exogenous cytokines. Alloreactive potential was evaluated based on proliferation, degranulation, cytotoxicity, and cytokine production. Further, their suppressive capacity was assessed by measuring inhibition of proliferating alloreactive CD28(+) T cells...
August 31, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28838649/brachytherapy-attains-abscopal-effects-when-combined-with-immunostimulatory-monoclonal-antibodies
#9
María E Rodriguez-Ruiz, Inmaculada Rodriguez, Benigno Barbes, Lina Mayorga, Alfonso Rodriguez Sanchez-Paulete, Mariano Ponz-Sarvise, José Luis Pérez-Gracia, Ignacio Melero
PURPOSE/OBJECTIVES: Preclinical and clinical evidence indicate that the proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory monoclonal antibodies (mAb) to act both on irradiated tumor lesions and on tumors at distant, nonirradiated sites. We have recently reported that external beam radiotherapy achieves abscopal effects when combined with antagonist anti-PD1 mAbs and agonist anti-CD137 (4-1BB) mAbs. The goal of this work is to study the abscopal effects of radiotherapy instigated by brachytherapy techniques...
August 21, 2017: Brachytherapy
https://www.readbyqxmd.com/read/28810809/optimization-of-human-nk-cell-manufacturing-fully-automated-separation-improved-ex-vivo-expansion-using-il-21-with-autologous-feeder-cells-and-generation-of-anti-cd123-car-expressing-effector-cells
#10
Stephan Klöß, Olaf Oberschmidt, Michael Morgan, Julia Dahlke, Lubomir Arseniev, Volker Huppert, Markus Granzin, Tanja Gardlowski, Nadine Matthies, Stephanie Soltenborn, Axel Schambach, Ulrike Koehl
The administration of ex vivo expanded natural killer (NK) cells as potential antitumor effector cells appears to be suitable for effector cell-based immunotherapies in high-risk cancer patients. However, good manufacturing practice (GMP)-compliant manufacturing of clinical-grade NK cells at sufficiently high numbers represents a great challenge. Therefore, previous expansion protocols for those effector cells were improved and optimized by using newly developed culture medium, interleukin (IL)-21, and autologous feeder cells (FCs)...
August 15, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28807877/cryptotanshinone-promotes-commitment-to-the-brown-adipocyte-lineage-and-mitochondrial-biogenesis-in-c3h10t1-2-mesenchymal-stem-cells-via-ampk-and-p38-mapk-signaling
#11
Khan Mohammad Imran, Naimur Rahman, Dahyeon Yoon, Miso Jeon, Byong-Taek Lee, Yong-Sik Kim
Although white adipose tissue (WAT) stores triglycerides and contributes to obesity, brown adipose tissue (BAT) dissipates energy as heat. Therefore, browning of WAT is regarded as an attractive way to counteract obesity. Our previous studies have revealed that treatment with cryptotanshinone (CT) during adipogenesis of 3T3-L1 cells inhibits their differentiation. Here, we found that pretreatment of C3H10T1/2 mesenchymal stem cells with CT before exposure to adipogenic hormonal stimuli promotes the commitment of these mesenchymal stem cells to the adipocyte lineage as confirmed by increased triglyceride accumulation...
October 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28798348/fas-ligand-mediated-cytotoxicity-of-cd4-t-cells-during-chronic-retrovirus-infection
#12
Anna Malyshkina, Elisabeth Littwitz-Salomon, Kathrin Sutter, Gennadiy Zelinskyy, Sonja Windmann, Simone Schimmer, Annette Paschen, Hendrik Streeck, Kim J Hasenkrug, Ulf Dittmer
CD4+ helper T cells and cytotoxic CD8+ T cells are key players for adaptive immune responses against acute infections with retroviruses. Similar to textbook knowledge the most important function of CD4+ T cells during an acute retrovirus infection seems to be their helper function for other immune cells. Whereas there was no direct anti-viral activity of CD4+ T cells during acute Friend Virus (FV) infection, they were absolutely required for the control of chronic infection. During chronic FV infection a population of activated FV-specific CD4+ T cells did not express cytotoxic molecules, but Fas Ligand that can induce Fas-induced apoptosis in target cells...
August 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28790118/anti-cd137-and-pd-1-pd-l1-antibodies-en-route-toward-clinical-synergy
#13
Elisabeth Pérez-Ruiz, Iñaki Etxeberria, Maria E Rodriguez-Ruiz, Ignacio Melero
T-cell costimulation and coinhibition can be respectively exploited by blocking and agonist mAbs. Both strategies can be synergistically combined in mouse models. Early clinical results from combinations of anti-PD-1 mAbs in conjunction with agonist anti-CD137 (4-1BB) mAbs show excellent safety and promising efficacy. Clin Cancer Res; 23(18); 1-3. ©2017 AACR.See related article by Tolcher et al., p. 5349.
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28771603/expression-of-pd-l1-and-other-immunotherapeutic-targets-in-thymic-epithelial-tumors
#14
Kathryn C Arbour, Jarushka Naidoo, Keith E Steele, Ai Ni, Andre L Moreira, Natasha Rekhtman, Paul B Robbins, Joyson Karakunnel, Andreas Rimner, James Huang, Gregory J Riely, Matthew D Hellmann
INTRODUCTION: The thymus is a critical organ for the development of the adaptive immune system and thymic epithelial tumors (TETs; thymomas and thymic carcinomas) are often associated with auto-immune paraneoplastic conditions. However, the immunobiology of TETs is not well described. An evaluation of the tumor microenvironment, with particular focus on expression of immunotherapeutic targets, may facilitate and prioritize development of immunotherapy strategies for patients with TETs...
2017: PloS One
https://www.readbyqxmd.com/read/28770466/cd137-cd137l-interaction-modulates-neointima-formation-and-the-phenotype-transformation-of-vascular-smooth-muscle-cells-via-nfatc1-signaling
#15
Wei Zhong, Bo Li, Ping Yang, Rui Chen, Cuiping Wang, Zhongqun Wang, Chen Shao, Wei Yuan, Jinchuan Yan
Vascular smooth muscle cell (VSMC) phenotype transformation is an important event in the formation of vessel neointima during lesion progression. CD137 can accelerate plaque formation, but the underlying mechanisms of this process remain unknown. Thus, we investigated the effect of CD137 signaling on VSMC phenotype transformation and potential mechanism underlying this transformation. Mouse recombinant CD137L and anti-CD137 antibody were used to activate or block the CD137 signaling way, respectively. Real-time PCR, immunofluorescence, and western blot analyses were performed to detect the expression of NFATc1 and phenotype markers such as SM-MHC, α-SMA, and vimentin in vivo or in vitro...
August 2, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28755037/novel-cd137-gene-polymorphisms-and-susceptibility-to-ischemic-stroke-in-the-northern-chinese-han-population
#16
Shuang Zhang, Zongmin Li, Ruyou Zhang, Xiaoying Li, Hewei Zheng, Qi Ma, Hui Zhang, Wenying Hou, Feng Zhang, Yingnan Wu, Litao Sun, Jiawei Tian
Ischemic stroke is a leading cause of mortality and morbidity worldwide, and atherosclerosis is one of the major risk factors for this neurologic deficit. Recent studies have revealed the important role of CD137 in human atherosclerosis. Here, we analyzed the association of CD137 single nucleotide polymorphisms (SNPs) with ischemic stroke. We assessed three SNPs (rs161827, rs161818, and rs161810) of the CD137 gene and their association with ischemic stroke in a northern Chinese Han population. A total of 496 ischemic stroke patients and 486 gender-matched control subjects were genotyped...
July 28, 2017: Neuromolecular Medicine
https://www.readbyqxmd.com/read/28747613/increased-carotid-artery-lesion-inflammation-upon-treatment-with-the-cd137-agonistic-antibody-2a
#17
Leif Å Söderström, Hong Jin, April S Caravaca, Maria L Klement, Yuhuang Li, Anton Gisterå, Ulf Hedin, Lars Maegdefessel, Göran K Hansson, Peder S Olofsson
BACKGROUND: Increased inflammatory activity destabilizes the atherosclerotic lesion and may lead to atherothrombosis and symptomatic cardiovascular disease. Co-stimulatory molecules, such as CD137, are key regulators of inflammation, and CD137 activity regulates inflammation in experimental atherosclerosis. Here, we hypothesized that CD137 activation promotes carotid artery inflammation and atherothrombosis.Methods and Results:In a model of inducible atherothrombosis with surgical ligation of the right carotid artery and a subsequent placement of a polyethene cuff, elevated levels of CD137 and CD137 ligand mRNA in atherothrombotic vs...
July 26, 2017: Circulation Journal: Official Journal of the Japanese Circulation Society
https://www.readbyqxmd.com/read/28660189/eosinophil-activation-status-in-separate-compartments-and-association-with-asthma
#18
REVIEW
Mats W Johansson
Asthma is frequently characterized by eosinophil-rich airway inflammation. Airway eosinophilia is associated with asthma exacerbations and likely plays a part in airway remodeling. Eosinophil recruitment from the bloodstream depends on circulating eosinophils becoming activated, which leads to eosinophil arrest on activated endothelium, extravasation, and continued movement through the bronchial tissue by interaction with the extracellular matrix (ECM). Circulating eosinophils can exist at different activation levels, which include non-activated or pre-activated (sensitized or "primed")...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28634283/phase-ib-study-of-utomilumab-pf-05082566-a-4-1bb-cd137-agonist-in-combination-with-pembrolizumab-mk-3475-in-patients-with-advanced-solid-tumors
#19
Anthony W Tolcher, Mario Sznol, Siwen Hu-Lieskovan, Kyriakos P Papadopoulos, Amita Patnaik, Drew W Rasco, Donna Di Gravio, Bo Huang, Dhiraj Gambhire, Ying Chen, Aron D Thall, Nuzhat Pathan, Emmett V Schmidt, Laura Q M Chow
Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with advanced solid tumors.Experimental Design: Utomilumab (0.45-5.0 mg/kg) and pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab dose escalation was conducted using the time-to-event continual reassessment method...
June 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28624961/phenotypic-and-functional-characterization-of-t-cells-in-white-matter-lesions-of-multiple-sclerosis-patients
#20
Gijsbert P van Nierop, Marvin M van Luijn, Samira S Michels, Marie-Jose Melief, Malou Janssen, Anton W Langerak, Werner J D Ouwendijk, Rogier Q Hintzen, Georges M G M Verjans
T cells are considered pivotal in the pathology of multiple sclerosis (MS), but their function and antigen specificity are unknown. To unravel the role of T cells in MS pathology, we performed a comprehensive analysis on T cells recovered from paired blood, cerebrospinal fluid (CSF), normal-appearing white matter (NAWM) and white matter lesions (WML) from 27 MS patients with advanced disease shortly after death. The differentiation status of T cells in these compartments was determined by ex vivo flow cytometry and immunohistochemistry...
June 17, 2017: Acta Neuropathologica
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