Judith Wienke, Laura Brouwers, Leone M van der Burg, Michal Mokry, Rianne C Scholman, Peter G J Nikkels, Bas B van Rijn, Femke van Wijk
Regulatory T cells (Tregs) are crucial for maintaining maternal immune-tolerance against the semi-allogeneic fetus. We investigated the elusive transcriptional profile and functional adaptation of human uterine Tregs (uTregs) during pregnancy. Uterine biopsies, from placental bed (=maternal-fetal interface) and incision site (=control), and blood were obtained from women with uneventful pregnancies undergoing Caesarean section. Tregs and CD4+ non-Tregs were isolated for transcriptomic profiling by Cel-Seq2...
August 18, 2020: JCI Insight
Keisuke Kazama, Toru Aoyama, Junya Otake, Manabu Shiozawa, Nobuhiro Sugano, Sumito Sato, Yosuke Atsumi, Kazuki Kano, Masaaki Murakawa, Yukio Maezawa, Itaru Hashimoto, Masakatsu Numata, Hiroshi Tamagawa, Takashi Oshima, Norio Yukawa, Yasushi Rino, Munetaka Masuda, Tetsuro Sasada
BACKGROUND/AIM: Tumor microenvironments consist of many types of immune cells, in which regulatory T-cells (Tregs) are supposed to play important roles to suppress anti-tumor immunity. Regional lymph nodes are essential for antitumor immunity in colorectal cancer (CRC). In this study, we compared the diversity of phenotypes of T-cells in normal tissue and regional lymph nodes in order to determine the immunosuppressive mechanism of lymph node metastasis of CRC. PATIENTS AND METHODS: Fifty patients were enrolled in this study, and paired samples (tumor tissue, normal tissue, and three regional lymph node samples and as well as non-regional lymph node samples) were obtained from each patient...
March 2020: In Vivo
Erminia Massarelli, Vincent K Lam, Edwin R Parra, Jaime Rodriguez-Canales, Carmen Behrens, Lixia Diao, Jing Wang, Jorge Blando, Lauren A Byers, Niranjan Yanamandra, Sara Brett, Peter Morley, Padmanee Sharma, James Allison, Ignacio I Wistuba, John V Heymach
INTRODUCTION: OX-40 co-stimulatory signaling plays a role in mounting anti-tumor immune responses and clinical trials targeting this pathway are ongoing. However, the association of with OX-40 protein expression with clinical outcomes and pathological features in non-small cell lung cancer (NSCLC) are largely unknown. METHODS: Surgically-resected stage I-III NSCLC specimens (N = 100) were stained by immunohistochemistry (IHC) for the following immune markers: OX-40, PD-L1, PD-1, CD3, CD4, CD8, CD45RO, CD57, CD68, FOXP3, granzyme B, and ICOS...
December 16, 2019: Journal for Immunotherapy of Cancer
Xiaojun Tang, Qi Tang, Yuan Mao, Xiaochen Huang, Lizhou Jia, Jin Zhu, Zhenqing Feng
Purpose: In previous research, we have found that LMP1-specific chimeric antigen (HELA/CAR) T cells can specifically recognize and kill LMP1-positive NPC cells. However, the tumor-inhibitory effectiveness of HELA/CART cells needs to be enhanced. Methods: We created two CARs that contain the T cell receptor-ζ (TCR-ζ) signal transduction domain with the CD28 and CD137 (4-1BB) or CD134 (OX-40) intracellular domains in tandem (HELA/137CAR or HELA/134CAR). Then, the tumor-inhibitory functions of two new CAR-T cells were investigated, both in vitro and in vivo...
2019: OncoTargets and Therapy
Hany A Omar, Mai F Tolba
In the new era of immunotherapy, which has changed the clinical oncology practice guidelines, there is a pressing need for finding novel approaches to tune up the clinical outcomes of immunotherapy and extend its benefits to a wider cohort of cancer patients. Several non-classical molecular immune targets beyond PD-1/PD-L1 signaling were shown to be engaged as feedback resistance circuits to shut down the antitumor immune response mediated by the classical immune checkpoint inhibitors. Those include T-cell inducible co-stimulator (ICOS), CD40, CD47, V-domain Ig suppressor of T-cell activation (VISTA), cyclin-dependent kinase (CDK)12, enhancer of Zeste homolog 2 (EZH2), toll-like receptors (TLRs) and OX-40 (CD134)...
March 2019: Critical Reviews in Oncology/hematology
Phyu P Aung, Edwin Roger Parra, Souptik Barua, Dawen Sui, Jing Ning, Barbara Mino, Debora Alejandra Ledesma, Jonathan L Curry, Priyadharsini Nagarajan, Carlos A Torres-Cabala, Eleni Efstathiou, Anh G Hoang, Michael K Wong, Jennifer A Wargo, Alexander J Lazar, Arvind Rao, Victor G Prieto, Ignacio Wistuba, Michael T Tetzlaff
PURPOSE: Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy whose pathogenesis and prognosis are related to the integrity of the host immune system. Despite promising clinical responses to immune-checkpoint blockade, response and resistance remain unpredictable, underscoring a critical need to delineate novel prognostic biomarkers and/or therapeutic targets for this disease. Experimental Design: Expression of immune-regulatory markers (PD-L2, B7-H3, B7-H4, IDO-1, ICOS, TIM3, LAG3, VISTA, and OX-40) was assessed using singlet chromogenic IHC in 10 primary MCCs...
June 1, 2019: Clinical Cancer Research
Javiera Gavilan, Daniela Mennickent, Oscar Ramirez-Molina, Sergio Triviño, Claudia Perez, Tiare Silva Grecchi, Pamela Godoy, Jose Becerra, Luis Aguayo, Gustavo Moraga, Victoria San Martin, Gonzalo Yevenes, Patricio Castro, Leonardo Guzman
Alzheimer's disease (AD) is a neurodegenerative pathology, which is characterized by progressive and irreversible cognitive impairment. Most of the neuronal perturbations described in AD can be associated with soluble amyloid- β oligomers (SO-Aβ). There is a large amount of evidence demonstrating the neuroprotective effect of Nicotine neurotransmission in AD, mainly through nicotinic acetylcholine receptor (nAChR) activation and antiapoptotic PI3K/Akt/Bcl-2 pathway signaling. Using HPLC and GC/MS, we isolated and characterized two alkaloids obtained from C...
December 19, 2018: Journal of Alzheimer's Disease: JAD
Christophe Pedros, Amnon Altman, Kok-Fai Kong
Follicular helper T (TFH ) cells represent a highly specialized CD4+ T cell subpopulation that supports the generation of germinal centers (GC) and provides B cells with critical signals promoting antibody class switching, generation of high affinity antibodies, and memory formation. TFH cells are characterized by the expression of the chemokine receptor CXCR5, the transcription factor Bcl-6, costimulatory molecules ICOS, and PD-1, and the production of cytokine IL-21. The acquisition of a TFH phenotype is a complex and multistep process that involves signals received through engagement of the TCR along with a multitude of costimulatory molecules and cytokines receptors...
2018: Frontiers in Immunology
Tomás Dalotto-Moreno, Ada G Blidner, M Romina Girotti, Sebastián M Maller, Gabriel A Rabinovich
Recent understanding of the mechanisms that control immune system homeostasis and orchestrate antitumor responses has prompted the development of novel immunotherapeutic modalities. These include antibodies that target immune checkpoints such as PD-1/PD-L1 and CTLA-4, agonistic antibodies of costimulatory molecules such as CD137 and OX-40 and the adoptive transfer of genetically-modified antitumor T cells. However, a large number of patients do not respond to these therapies and develop resistance as a result of activation of compensatory circuits...
2018: Medicina
Jingjing Duan, Yongwei Xie, Lijuan Qu, Lingxiong Wang, Shunkai Zhou, Yu Wang, Zhongyi Fan, Shengsheng Yang, Shunchang Jiao
BACKGROUND: Immunoscore, as a prognostic tool defined to quantify in situ immune cell infiltrates, appears to be superior to the TNM staging system. In esophageal squamous cell carcinoma (ESCC), no immunoscore has been established; however, in situ tumor immunology is recognized as highly important. Our study aimed to construct a comprehensive immunoprofile for ESCC. METHODS: The infiltration of four immune cell types (CD8+/CD4+/Foxp3+/CD33+ cells), the expression of both inhibitory (PD-1/PD-L1/Tim-3/LAG-3) and stimulatory checkpoints (OX-40/ICOS), and IDO1 were evaluated by IHC staining and multi-color immunofluorescence in two independent cohorts (95 patients in the primary cohort and 55 patients in the validation cohort)...
October 3, 2018: Journal for Immunotherapy of Cancer
Ronit Mazor, Emily King, Ira Pastan
LMB-100 is a recombinant immunotoxin being developed for cancer treatment that is composed of a Fab that binds to mesothelin and a portion of Pseudomonas exotoxin A. LMB-100 is in clinical trials for the treatment of mesothelioma and pancreatic cancer. To determine if check point modulating antibodies enhance the formation of anti-drug antibodies (ADA) against LMB-100, we treated mice with LMB-100 and four different immune modulating monoclonal antibodies that have different mechanisms of action; anti-CTLA4, anti-OX40, anti-PD-1 and anti-PDL-1...
December 2018: Cellular Immunology
Eric C Ko, David Raben, Silvia C Formenti
Five-year survival rates for non-small cell lung cancer (NSCLC) range from 14% to 49% for stage I to stage IIIA disease, and are <5% for stage IIIB/IV disease. Improvements have been made in the outcomes of patients with NSCLC due to advancements in radiotherapy (RT) techniques, the use of concurrent chemotherapy with RT, and the emergence of immunotherapy as first- and second-line treatment in the metastatic setting. RT remains the mainstay treatment in patients with inoperable early-stage NSCLC and is given concurrently or sequentially with chemotherapy in patients with locally advanced unresectable disease...
December 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Lukose K Thampy, Kenneth E Remy, Andrew H Walton, Zachery Hong, Kelilah Liu, Rebecca Liu, Victoria Yi, Carey-Ann D Burnham, Richard S Hotchkiss
BACKGROUND: Multidrug resistant (MDR) bacterial pathogens are a serious problem of increasing importance facing the medical community. MDR bacteria typically infect the most immunologically vulnerable: patients in intensive care units, patients with extensive comorbidities, oncology patients, hemodialysis patients, and other immune suppressed individuals are likely to fall victim to these pathogens. One promising novel approach to treatment of MDR bacteria is immuno-adjuvant therapy to boost patient immunity...
2018: PloS One
Mário R Martins, Rogério L D Santos, Kleber D N Jatahy, Marina C D Matta, Thales P Batista, José Iran C Júnior, Maria D F S Begnami, Leuridan C Torres
BACKGROUND AND OBJECTIVES: OX40, a membrane-bound molecule of the tumor-necrosis-factor-receptor superfamily, is a critical costimulatory receptor during the immune response, especially to T cells, but studies described their presence of OX-40 on neutrophils and monocytes, suggesting a potential role in the activation of immune response. Our aim was to characterize costimulatory receptors OX40 expression on circulating leukocytes in gastric cancer to identify novel targets for immunotherapy...
April 2018: Journal of Surgical Oncology
Sathana Dushyanthen, Zhi Ling Teo, Franco Caramia, Peter Savas, Christopher P Mintoff, Balaji Virassamy, Melissa A Henderson, Stephen J Luen, Mariam Mansour, Michael H Kershaw, Joseph A Trapani, Paul J Neeson, Roberto Salgado, Grant A McArthur, Justin M Balko, Paul A Beavis, Phillip K Darcy, Sherene Loi
The presence of tumor-infiltrating lymphocytes in triple-negative breast cancers is correlated with improved outcomes. Ras/MAPK pathway activation is associated with significantly lower levels of tumor-infiltrating lymphocytes in triple-negative breast cancers and while MEK inhibition can promote recruitment of tumor-infiltrating lymphocytes to the tumor, here we show that MEK inhibition adversely affects early onset T-cell effector function. We show that α-4-1BB and α-OX-40 T-cell agonist antibodies can rescue the adverse effects of MEK inhibition on T cells in both mouse and human T cells, which results in augmented anti-tumor effects in vivo...
September 19, 2017: Nature Communications
Ercan Cacan
The immunological response against cancer is a critical balance between immune-activating and immune-suppressing mechanisms. Ovarian cancer creates a suppressive microenvironment to escape immune elimination; however, the molecular mechanisms are poorly understood, and it is unclear whether chemotherapeutic drugs exert an immunoreactive or immunosuppressive effect on the tumor microenvironment. 4-1BB ligand (4-1BBL/CD157) and OX-40 ligand (OX-40L/CD252) are important regulators of effector cytotoxic T-cells activity...
March 2017: Cell Biology International
Bettina Langhans, Hans Dieter Nischalke, Benjamin Krämer, Annekristin Hausen, Leona Dold, Peer van Heteren, Robert Hüneburg, Jacob Nattermann, Christian P Strassburg, Ulrich Spengler
BACKGROUND & AIMS: CD4(+) regulatory T cells (Tregs) expand during chronic hepatitis C virus (HCV) infection, inhibit antiviral immunity and promote fibrosis. Direct-acting antiviral agents (DAA) have revolutionized HCV therapy. However, it is unclear if Tregs are normalized after DAA-induced HCV elimination. METHODS: We analyzed Tregs before (baseline), at end of therapy (EOT), 12 and 24weeks (SVR12, SVR24) and long-term (51±14weeks) after EOT in 26 genotype-1-infected patients who were successfully treated with sofosbuvir (SOF) plus interferon (IFN)/ribavirin (n=12) and IFN-free DAA regimens (SOF plus daclatasvir or simeprevir; n=14)...
May 2017: Journal of Hepatology
Tzu-Yu Shao, Ling-Hui Hsu, Chien-Hui Chien, Bor-Luen Chiang
Recent studies have revealed various Foxp3(-) regulatory T (Treg) cell subsets effectively protect mice from colitis. In the present study, we demonstrated that B cells induced a particular subset of regulatory T (Treg-of-B) cells, expressing programmed cell death 1 (PD-1), inducible costimulator (ICOS), lymphocyte-activation gene 3 (LAG3), glucocorticoid-induced tumor necrosis factor receptor (GITR), and OX-40, did not express Foxp3. Treg-of-B cells produced abundant levels of IL-10 and low levels of IL-4 and TGF-β...
September 1, 2016: Scientific Reports
Se Jin Im, Masao Hashimoto, Michael Y Gerner, Junghwa Lee, Haydn T Kissick, Matheus C Burger, Qiang Shan, J Scott Hale, Judong Lee, Tahseen H Nasti, Arlene H Sharpe, Gordon J Freeman, Ronald N Germain, Helder I Nakaya, Hai-Hui Xue, Rafi Ahmed
Chronic viral infections are characterized by a state of CD8+ T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8+ T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8+ T cells. Here we identify a population of virus-specific CD8+ T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV)...
September 15, 2016: Nature
Guillaume Froehlicher, Etienne Lorchat, François Fernique, Chaitanya Joshi, Alejandro Molina-Sánchez, Ludger Wirtz, Stéphane Berciaud
N-layer transition metal dichalcogenides provide a unique platform to investigate the evolution of the physical properties between the bulk (three-dimensional) and monolayer (quasi-two-dimensional) limits. Here, using high-resolution micro-Raman spectroscopy, we report a unified experimental description of the Γ-point optical phonons in N-layer 2H-molybdenum ditelluride (MoTe2). We observe series of N-dependent low-frequency interlayer shear and breathing modes (below 40 cm(-1), denoted LSM and LBM) and well-defined Davydov splittings of the mid-frequency modes (in the range 100-200 cm(-1), denoted iX and oX), which solely involve displacements of the chalcogen atoms...
October 14, 2015: Nano Letters
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