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https://www.readbyqxmd.com/read/29784675/radiation-followed-by-ox40-stimulation-drives-local-and-abscopal-antitumor-effects-in-an-anti-pd1-resistant-lung-tumor-model
#1
Sharareh Niknam, Hampartsoum B Barsoumian, Jonathan E Schoenhals, Heather Jackson, Niranjan Yanamandra, Mauricio S Caetano, Ailin Li, Ahmed I Younes, Alexandra P Cadena, Taylor R Cushman, Joe Y Chang, Quynh Nguyen, Daniel R Gomez, Adi Diab, John V Heymach, Patrick Hwu, Maria Angelica Cortez, James W Welsh
PURPOSE: Radiation is used extensively to treat localized cancer, but improved understanding of its effects on the immune system have increased interest in its potential systemic (abscopal) effects, particularly in combination with checkpoint inhibitors such as anti-PD1. The majority of patients either do not respond or develop resistance to monotherapy over time. Here, we investigated the efficacy of OX40 (CD134) stimulation as an alternative immunotherapeutic approach in combination with radiotherapy (XRT) in a murine model of anti-PD1-resistant lung tumors...
May 21, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29773890/intraperitoneal-administration-of-the-anti-il-23-antibody-prevents-the-establishment-of-intestinal-nematodes-in-mice
#2
M Gomez-Samblas, D Bernal, A Bolado-Ortiz, S Vilchez, F Bolás-Fernández, A M Espino, M Trelis, A Osuna
Previous studies have established that an increased Th-9 response creates a hostile environment for nematode parasites. Given that IL-23, a cytokine required for maintenance of the IL-17-secreting phenotype, has inhibitory effects on IL-9 production, we hypothesized that reducing circulating IL-23 by treatment with anti-IL-23 antibodies would reduce the establishment and development of parasitic intestinal nematodes. In this study, we show that animals treated with anti-IL-23 monoclonal antibodies showed a drastic reduction in the number of mouse pinworms (Aspiculuris tetraptera) recovered from the intestine (p < 0...
May 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29751636/design-synthesis-and-evaluation-of-novel-immunomodulatory-small-molecules-targeting-the-cd40%C3%A2-cd154-costimulatory-protein-protein-interaction
#3
Damir Bojadzic, Jinshui Chen, Oscar Alcazar, Peter Buchwald
We report the design, synthesis, and testing of novel small-molecule compounds targeting the CD40⁻CD154 (CD40L) costimulatory interaction for immunomodulatory purposes. This protein-protein interaction (PPI) is a TNF-superfamily (TNFSF) costimulatory interaction that is an important therapeutic target since it plays crucial roles in the activation of T cell responses, and there is resurgent interest in its modulation with several biologics in development. However, this interaction, just as all other PPIs, is difficult to target by small molecules...
May 11, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29721382/expression-of-llt1-and-its-receptor-cd161-in-lung-cancer-is-associated-with-better-clinical-outcome
#4
Véronique M Braud, Jérôme Biton, Etienne Becht, Samantha Knockaert, Audrey Mansuet-Lupo, Estelle Cosson, Diane Damotte, Marco Alifano, Pierre Validire, Fabienne Anjuère, Isabelle Cremer, Nicolas Girard, Dominique Gossot, Agathe Seguin-Givelet, Marie-Caroline Dieu-Nosjean, Claire Germain
Co-stimulatory and inhibitory receptors expressed by immune cells in the tumor microenvironment modulate the immune response and cancer progression. Their expression and regulation are still not fully characterized and a better understanding of these mechanisms is needed to improve current immunotherapies. Our previous work has identified a novel ligand/receptor pair, LLT1/CD161, that modulates immune responses. Here, we extensively characterize its expression in non-small cell lung cancer (NSCLC). We show that LLT1 expression is restricted to germinal center (GC) B cells within tertiary lymphoid structures (TLS), representing a new hallmark of the presence of active TLS in the tumor microenvironment...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29701145/a-potential-therapeutic-target-rna-binding-protein-arid5a-for-the-treatment-of-inflammatory-disease-associated-with-aberrant-cytokine-expression
#5
Kazuya Masuda, Tadamitsu Kishimoto
BACKGROUND: Infection, tissue damage and aging can cause inflammation with high levels of inflammatory cytokines. Overproduction of inflammatory cytokines often leads to systemic inflammatory response syndrome (SIRS), severe sepsis, and septic shock. However, prominent therapeutic targets have not been found, although the incidence of sepsis is likely to increase annually. Our recent studies indicate that some RNA-binding proteins, which control gene expression of inflammatory cytokines at the post-transcriptional level, may play a critical role in inflammatory diseases such as sepsis...
April 25, 2018: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/29700419/the-correlation-between-the-immune-and-epithelial-mesenchymal-transition-signatures-suggests-potential-therapeutic-targets-and-prognosis-prediction-approaches-in-kidney-cancer
#6
Jiayu Liang, Zhihong Liu, Zijun Zou, Yongquan Tang, Chuan Zhou, Jian Yang, Xin Wei, Yiping Lu
Both epithelial-mesenchymal transition (EMT) and immune regulation are important biological process in malignant tumours. The current research aims to comprehensively explore the potential association between the epithelial-mesenchymal transition (EMT) signature and immune checkpoint signature and its role in predicting the prognosis of clear-cell renal cell carcinoma (ccRCC) patients. EMT-related genes were collected from an experiment-based study and then were investigated using data from the Cancer Genome Atlas...
April 26, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29670037/expression-and-regulation-of-thymic-stromal-lymphopoietin-and-thymic-stromal-lymphopoietin-receptor-heterocomplex-in-the-innate-adaptive-immunity-of-pediatric-asthma
#7
REVIEW
Sheng-Chieh Lin, Fang-Yi Cheng, Jun-Jen Liu, Yi-Ling Ye
Asthma is a chronic inflammatory disease affecting the airway, and it is characterized by a wheezing breathing sound, variable airflow obstruction and the presence of inflammatory cells in the submucosa of the bronchi. Viral infection, pollutants and sensitivity to aeroallergens damage the epithelium from childhood, which causes asthma. The pathogenesis of asthma includes pathways of innate stimulation by environmental microbes and irritant pathogens. Damaged epithelial cells produce thymic stromal lymphopoietin (TSLP) and stimulate myeloid dendritic cell maturation through the thymic stromal lymphopoietin receptor (TSLPR) heterocomplex...
April 18, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29668708/dectin-1-2-induced-autocrine-pge2-signaling-licenses-dendritic-cells-to-prime-th2-responses
#8
Maria M M Kaisar, Manuel Ritter, Carlos Del Fresno, Hulda S Jónasdóttir, Alwin J van der Ham, Leonard R Pelgrom, Gabriele Schramm, Laura E Layland, David Sancho, Clarissa Prazeres da Costa, Martin Giera, Maria Yazdanbakhsh, Bart Everts
The molecular mechanisms through which dendritic cells (DCs) prime T helper 2 (Th2) responses, including those elicited by parasitic helminths, remain incompletely understood. Here, we report that soluble egg antigen (SEA) from Schistosoma mansoni, which is well known to drive potent Th2 responses, triggers DCs to produce prostaglandin E2 (PGE2), which subsequently-in an autocrine manner-induces OX40 ligand (OX40L) expression to license these DCs to drive Th2 responses. Mechanistically, SEA was found to promote PGE2 synthesis through Dectin-1 and Dectin-2, and via a downstream signaling cascade involving spleen tyrosine kinase (Syk), extracellular signal-regulated kinase (ERK), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase 1 and 2 (COX-1 and COX-2)...
April 18, 2018: PLoS Biology
https://www.readbyqxmd.com/read/29661166/high-ox40-expression-in-recurrent-ovarian-carcinoma-is-indicative-for-response-to-repeated-chemotherapy
#9
Michaela Ramser, Simone Eichelberger, Silvio Däster, Benjamin Weixler, Marko Kraljević, Robert Mechera, Athanasios Tampakis, Tarik Delko, Uwe Güth, Sylvia Stadlmann, Luigi Terracciano, Raoul A Droeser, Gad Singer
BACKGROUND: Ovarian carcinoma (OC) is the fifth most common female cancer and mostly diagnosed at an advanced stage. Surgical debulking is usually followed by adjuvant platinum-based chemotherapy. Only few biomarkers are known to be related to chemosensitivity. OX40 is a TNF receptor member and expressed on activated CD4+ and CD8+ T cells. It is known that OX40 signaling promotes survival and responds to various immune cells of the innate and adaptive immune system. Therefore we investigated the indicative value of OX40 expression for recurrence and survival in OC...
April 16, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29628925/human-endothelial-cells-modulate-cd4-t-cell-populations-and-enhance-regulatory-t-cell-suppressive-capacity
#10
Wen Chean Lim, Michael Olding, Eugene Healy, Timothy M Millar
Endothelial cells (ECs) line the luminal surface of blood vessels and have an active role in the recruitment of leukocytes, including immune cell activation. Regulatory T cells (Tregs) are immune suppressor cells that maintain peripheral tolerance and must interact with the endothelium as they traffic into tissue. We hypothesized that human ECs could modulate Tregs and their suppressor function. Cocultures of CD4+ T cells with human umbilical vein ECs (HUVECs) or dermal microvascular ECs (HDMECs) were conducted and analyzed for activation and proliferation after 72 and 120 h using flow cytometry...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29622809/viral-hepatitis-ox40-signalling-mediates-effective-hbv-immune-responses
#11
Hugh Thomas
No abstract text is available yet for this article.
May 2018: Nature Reviews. Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/29596062/imaging-activated-t-cells-predicts-response-to-cancer-vaccines
#12
Israt S Alam, Aaron T Mayer, Idit Sagiv-Barfi, Kezheng Wang, Ophir Vermesh, Debra K Czerwinski, Emily M Johnson, Michelle L James, Ronald Levy, Sanjiv S Gambhir
In situ cancer vaccines are under active clinical investigation due to their reported ability to eradicate both local and disseminated malignancies. Intratumoral vaccine administration is thought to activate a T cell mediated immune response, which begins in the treated tumor and cascades systemically. We describe a positron emission tomography tracer (64Cu-DOTA-AbOX40) that enabled non-invasive and longitudinal imaging of OX40, a cell surface marker of T cell activation. We report the spatiotemporal dynamics of T cell activation following in situ vaccination with CpG oligodeoxynucleotide, in a dual tumor bearing mouse model...
March 29, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29578532/critical-role-of-ox40-signaling-in-the-tcr-independent-phase-of-human-and-murine-thymic-treg-generation
#13
Prabhakaran Kumar, Alejandra Marinelarena, Divya Raghunathan, Vandhana K Ragothaman, Shikha Saini, Palash Bhattacharya, Jilao Fan, Alan L Epstein, Ajay V Maker, Bellur S Prabhakar
Regulatory T cells (Tregs) play a pivotal role in immune-tolerance, and loss of Treg function can lead to the development of autoimmunity. Natural Tregs generated in the thymus substantially contribute to the Treg pool in the periphery, where they suppress self-reactive effector T cells (Teff) responses. Recently, we showed that OX40L (TNFSF4) is able to drive selective proliferation of peripheral Tregs independent of canonical antigen presentation (CAP-independent) in the presence of low-dose IL-2. Therefore, we hypothesized that OX40 signaling might be integral to the TCR-independent phase of murine and human thymic Treg (tTreg) development...
March 26, 2018: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/29574275/anti-cd73-and-anti-ox40-immunotherapy-coupled-with-a-novel-biocompatible-enzyme-prodrug-system-for-the-treatment-of-recurrent-metastatic-ovarian-cancer
#14
Needa A Virani, Elangovan Thavathiru, Patrick McKernan, Kathleen Moore, Doris M Benbrook, Roger G Harrison
Approximately 75% of ovarian cancer is diagnosed once metastasis to the peritoneal cavity has occurred. A large proportion of patients eventually develop platinum-resistive tumors, which are considered terminal. In order to provide an alternative a novel fusion protein, mCTH-ANXA5, has been developed for the treatment of recurrent, metastatic ovarian cancer. The fusion protein combines annexin V (ANXA5), an ovarian tumor and tumor vasculature targeting protein, with mutated cystathionine gamma-lyase (mCTH), an enzyme that converts selenomethionine (SeMet) into toxic methylselenol, which generates reactive oxygen species and eventual tumor cell death...
March 21, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29563320/an-ox40-ox40l-interaction-directs-successful-immunity-to-hepatitis-b-virus
#15
Jean Publicover, Anuj Gaggar, Jillian M Jespersen, Ugur Halac, Audra J Johnson, Amanda Goodsell, Lia Avanesyan, Stephen L Nishimura, Meghan Holdorf, Keith G Mansfield, Joyce Bousquet Judge, Arya Koshti, Michael Croft, Adil E Wakil, Philip Rosenthal, Eric Pai, Stewart Cooper, Jody L Baron
Depending on age of acquisition, hepatitis B virus (HBV) can induce a cell-mediated immune response that results in either cure or progressive liver injury. In adult-acquired infection, HBV antigens are usually cleared, whereas in infancy-acquired infection, they persist. Individuals infected during infancy therefore represent the majority of patients chronically infected with HBV (CHB). A therapy that can promote viral antigen clearance in most CHB patients has not been developed and would represent a major health care advance and cost mitigator...
March 21, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29554934/ox40l-induces-helper-t-cell-differentiation-during-cell-immunity-of-asthma-through-pi3k-akt-and-p38-mapk-signaling-pathway
#16
Li Huang, Meijuan Wang, Yongdong Yan, Wenjing Gu, Xinxing Zhang, Jiahong Tan, Huiming Sun, Wei Ji, Zhengrong Chen
BACKGROUND: The aim of this study was to investigate the mechanisms of OX40L in regulating helper T (Th) cells differentiation through phosphoinositide 3-kinase (PI3K)/AKT and p38 mitogen-activated protein kinase signaling pathway in vitro and in vivo experiments. METHODS: Serum samples of patients with asthma and healthy controls were used to explore the association between OX40L and Th cells. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum concentrations of OX40L, IL-4, IFN-γ, IL-17 and TGF-β...
March 20, 2018: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29550278/tslp-activated-dendritic-cells-induce-t-helper-type-2-inflammation-in-aspergillus-fumigatus-keratitis
#17
Lin Sun, Chen Chen, Jiayin Wu, Chenyang Dai, Xinyi Wu
Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine, which is secreted by epithelial cells under the stimulation of Toll-like receptor (TLR) ligands. Dendritic cells (DCs) which express the thymic stromal lymphopoietin receptor (TSLPR) can be activated by TSLP. Mature DCs can express the OX40 ligand, which has the ability to combine with OX40 on the surface of T cells to stimulate T cell proliferation. TSLP secreted by corneal epithelial cells can engage in the process of T helper type 2 (Th2) inflammation in Aspergillus fumigatus keratitis, but the mechanism remains unclear...
June 2018: Experimental Eye Research
https://www.readbyqxmd.com/read/29545330/potent-immune-modulation-by-medi6383-an-engineered-human-ox40-ligand-igg4p-fc-fusion-protein
#18
Michael D Oberst, Catherine Augé, Chad Morris, Stacy Kentner, Kathy Mulgrew, Kelly McGlinchey, James Hair, Shino Hanabuchi, Qun Du, Melissa Damschroder, Hui Feng, Steven Eck, Nicholas Buss, Lolke de Haan, Andrew J Pierce, Haesun Park, Andrew Sylwester, Michael K Axthelm, Louis Picker, Nicholas P Morris, Andrew Weinberg, Scott A Hammond
Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells...
May 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29544515/next-generation-of-immune-checkpoint-therapy-in-cancer-new-developments-and-challenges
#19
REVIEW
Julian A Marin-Acevedo, Bhagirathbhai Dholaria, Aixa E Soyano, Keith L Knutson, Saranya Chumsri, Yanyan Lou
Immune checkpoints consist of inhibitory and stimulatory pathways that maintain self-tolerance and assist with immune response. In cancer, immune checkpoint pathways are often activated to inhibit the nascent anti-tumor immune response. Immune checkpoint therapies act by blocking or stimulating these pathways and enhance the body's immunological activity against tumors. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1(PD-L1) are the most widely studied and recognized inhibitory checkpoint pathways...
March 15, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29529339/could-ox40-agonist-antibody-promote-activation-of-the-anti-tumor-immune-response-in-gastric-cancer
#20
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...
March 12, 2018: Journal of Surgical Oncology
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