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https://www.readbyqxmd.com/read/29137299/tumor-expressed-immune-checkpoint-b7x-promotes-cancer-progression-and-antigen-specific-cd8-t-cell-exhaustion-and-suppressive-innate-immune-cells
#1
Kim C Ohaegbulam, Weifeng Liu, Hyungjun Jeon, Steven C Almo, Xingxing Zang
B7x (B7-H4 or B7S1) is a coinhibitory member of the B7 immune checkpoint ligand family that regulates immune function following ligation with its unknown cognate receptors. B7x has limited expression on normal tissues, but is up-regulated on solid human tumors to inhibit anti-tumor immunity and associates with poor clinical prognosis. We assessed the contribution of cytokine stimuli to induce surface B7x expression on cancer cells and the role of tumor-expressed B7x in a murine pulmonary metastasis model, and finally evaluated the potential interaction between B7x and Neuropilin-1, a suggested potential cognate receptor...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29126798/cd4-t-cell-help-confers-a-cytotoxic-t-cell-effector-program-including-coinhibitory-receptor-downregulation-and-increased-tissue-invasiveness
#2
Tomasz Ahrends, Aldo Spanjaard, Bas Pilzecker, Nikolina Bąbała, Astrid Bovens, Yanling Xiao, Heinz Jacobs, Jannie Borst
CD4(+) T cells optimize the cytotoxic T cell (CTL) response in magnitude and quality, by unknown molecular mechanisms. We here present the transcriptomic changes in CTLs resulting from CD4(+) T cell help after anti-cancer vaccination or virus infection. The gene expression signatures revealed that CD4(+) T cell help during priming optimized CTLs in expression of cytotoxic effector molecules and many other functions that ensured efficacy of CTLs throughout their life cycle. Key features included downregulation of PD-1 and other coinhibitory receptors that impede CTL activity, and increased motility and migration capacities...
November 6, 2017: Immunity
https://www.readbyqxmd.com/read/29109121/glycogen-synthase-kinase-3-modulates-cbl-b-and-constrains-t-cell-activation
#3
Charles W Tran, Samuel D Saibil, Thierry Le Bihan, Sara R Hamilton, Karl S Lang, Han You, Amy E Lin, Kristine M Garza, Alisha R Elford, Kelly Tai, Michael E Parsons, Kip Wigmore, Mitchell G Vainberg, Josef M Penninger, James R Woodgett, Tak W Mak, Pamela S Ohashi
The decision between T cell activation and tolerance is governed by the spatial and temporal integration of diverse molecular signals and events occurring downstream of TCR and costimulatory or coinhibitory receptor engagement. The PI3K-protein kinase B (PKB; also known as Akt) signaling pathway is a central axis in mediating proximal signaling events of TCR and CD28 engagement in T cells. Perturbation of the PI3K-PKB pathway, or the loss of negative regulators of T cell activation, such as the E3 ubiquitin ligase Cbl-b, have been reported to lead to increased susceptibility to autoimmunity...
November 6, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29101312/gingival-tissue-inflammation-promotes-increased-matrix-metalloproteinase-12-production-by-cd200r-low-monocyte-derived-cells-in-periodontitis
#4
Sofia Björnfot Holmström, Reuben Clark, Stephanie Zwicker, Daniela Bureik, Egle Kvedaraite, Eric Bernasconi, Anh Thu Nguyen Hoang, Gunnar Johannsen, Benjamin J Marsland, Elisabeth A Boström, Mattias Svensson
Irreversible tissue recession in chronic inflammatory diseases is associated with dysregulated immune activation and production of tissue degradative enzymes. In this study, we identified elevated levels of matrix metalloproteinase (MMP)-12 in gingival tissue of patients with the chronic inflammatory disease periodontitis (PD). The source of MMP12 was cells of monocyte origin as determined by the expression of CD14, CD68, and CD64. These MMP12-producing cells showed reduced surface levels of the coinhibitory molecule CD200R...
November 3, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29099676/molecular-and-genomic-determinants-of-response-to-immune-checkpoint-inhibition-in-cancer
#5
Russell W Jenkins, Rohit Thummalapalli, Jacob Carter, Israel Cañadas, David A Barbie
Molecularly targeted therapy and immunotherapy have dramatically changed the landscape of available treatment options for patients with advanced cancer. Improved understanding of the molecular and genomic features of cancers over the last decade has led to the development of successful targeted therapies and the field of precision cancer medicine. As a result of these advances, patients whose tumors harbor select molecular alterations are eligible for treatment with targeted therapies active against the unique molecular aberration...
November 3, 2017: Annual Review of Medicine
https://www.readbyqxmd.com/read/29097600/pd-l1
#6
REVIEW
Anthousa Kythreotou, Abdul Siddique, Francesco A Mauri, Mark Bower, David J Pinato
Programmed death ligand 1 (PD-L1) is the principal ligand of programmed death 1 (PD-1), a coinhibitory receptor that can be constitutively expressed or induced in myeloid, lymphoid, normal epithelial cells and in cancer. Under physiological conditions, the PD-1/PD-L1 interaction is essential in the development of immune tolerance preventing excessive immune cell activity that can lead to tissue destruction and autoimmunity. PD-L1 expression is an immune evasion mechanism exploited by various malignancies and is generally associated with poorer prognosis...
November 2, 2017: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/29092744/dual-requirement-for-stat-signaling-in-dendritic-cell-immunobiology
#7
Gloria Donninelli, Isabella Sanseverino, Cristina Purificato, Sandra Gessani, Maria Cristina Gauzzi
Dendritic cells (DC) represent an attractive target for therapeutic manipulation of the immune system and enhancement of insufficient immune response in cancer. STAT family members play key roles in the differentiation and activation of DC, a feature that is currently being exploited in DC-based therapies. We previously reported that the small-molecule Stattic, originally developed as a STAT3-specific inhibitor, also inhibits STAT1 and STAT2 phosphorylation in DC exposed to cytokines or LPS. Aim of this study was to investigate the functional consequences of in vitro treatment with Stattic on DC immunobiology...
October 27, 2017: Immunobiology
https://www.readbyqxmd.com/read/29065967/pd-1-deficiency-protects-experimental-colitis-via-alteration-of-gut-microbiota
#8
Seong Jeong Park, Ji-Hae Kim, Mi-Young Song, Young Chul Sung, Seung-Woo Lee, Yunji Park
Programmed cell death-1 (PD-1) is a coinhibitory molecule and plays a pivotal role in immune regulation. Here, we demonstrate a role for PD-1 in pathogenesis of inflammatory bowel disease (IBD). Wild-type (WT) mice had severe wasting disease during experimentally induced colitis, while mice deficient for PD-1 (PD-1-/-) did not develop colon inflammation. Interestingly, PD-1-/- mice cohoused with WT mice became susceptible to colitis, suggesting that resistance of PD-1-/- mice to colitis is dependent on their gut microbiota...
October 25, 2017: BMB Reports
https://www.readbyqxmd.com/read/29033936/coinhibitory-receptor-expression-and-immune-checkpoint-blockade-maintaining-a-balance-in-cd8-t-cell-responses-to-chronic-viral-infections-and-cancer
#9
REVIEW
Isobel S Okoye, Michael Houghton, Lorne Tyrrell, Khaled Barakat, Shokrollah Elahi
In cancer and chronic viral infections, T cells are exposed to persistent antigen stimulation. This results in expression of multiple inhibitory receptors also called "immune checkpoints" by T cells. Although these inhibitory receptors under normal conditions maintain self-tolerance and prevent immunopathology, their sustained expression deteriorates T cell function: a phenomenon called exhaustion. Recent advances in cancer immunotherapy involve blockade of cytotoxic T lymphocyte antigen-4 and programmed cell death 1 in order to reverse T cell exhaustion and reinvigorate immunity, which has translated to dramatic clinical remission in many cases of metastatic melanoma and lung cancer...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29029399/a-cellular-platform-for-the-evaluation-of-immune-checkpoint-molecules
#10
Sabrina Jutz, Annika Hennig, Wolfgang Paster, Ömer Asrak, Dejana Dijanovic, Florian Kellner, Winfried F Pickl, Johannes B Huppa, Judith Leitner, Peter Steinberger
Blockade of the T cell coinhibitory molecules CTLA-4 and PD-1 has clinical utility to strengthen T cell responses. In addition to these immune checkpoints an ever-growing number of molecules has been implicated in generating coinhibitory signals in T cells. However, investigating coinhibitory molecules in primary human cells is complicated by the restricted expression and promiscuity of both coinhibitory receptors and their ligands. Here we have evaluated the potential of fluorescence-based transcriptional reporters based on the human Jurkat T cell line in conjunction with engineered T cell stimulator cell lines for investigating coinhibitory pathways...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28990585/the-diverse-functions-of-the-pd1-inhibitory-pathway
#11
REVIEW
Arlene H Sharpe, Kristen E Pauken
T cell activation is a highly regulated process involving peptide-MHC engagement of the T cell receptor and positive costimulatory signals. Upon activation, coinhibitory 'checkpoints', including programmed cell death protein 1 (PD1), become induced to regulate T cells. PD1 has an essential role in balancing protective immunity and immunopathology, homeostasis and tolerance. However, during responses to chronic pathogens and tumours, PD1 expression can limit protective immunity. Recently developed PD1 pathway inhibitors have revolutionized cancer treatment for some patients, but the majority of patients do not show complete responses, and adverse events have been noted...
October 9, 2017: Nature Reviews. Immunology
https://www.readbyqxmd.com/read/28978798/selective-blockade-of-cd28-on-human-t-cells-facilitates-regulation-of-alloimmune-responses
#12
Masaaki Zaitsu, Fadi Issa, Joanna Hester, Bernard Vanhove, Kathryn J Wood
T cells are central to the detrimental alloresponses that develop in autoimmunity and transplantation, with CD28 costimulatory signals being key to T cell activation and proliferation. CTLA4-Ig molecules that bind CD80/86 and inhibit CD28 costimulation offer an alternative immunosuppressive treatment, free from some of the chronic toxicities associated with calcineurin inhibition. However, CD80/86 blockade by CTLA4-Ig also results in the loss of coinhibitory CTLA4 signals that are critical to the regulation of T cell activation...
October 5, 2017: JCI Insight
https://www.readbyqxmd.com/read/28939757/pd-1-blockade-promotes-epitope-spreading-in-anticancer-cd8-t-cell-responses-by-preventing-fratricidal-death-of-subdominant-clones-to-relieve-immunodomination
#13
Arash Memarnejadian, Courtney E Meilleur, Christopher R Shaler, Khashayarsha Khazaie, Jack R Bennink, Todd D Schell, S M Mansour Haeryfar
The interactions between programmed death-1 (PD-1) and its ligands hamper tumor-specific CD8(+) T cell (TCD8) responses, and PD-1-based "checkpoint inhibitors" have shown promise in certain cancers, thus revitalizing interest in immunotherapy. PD-1-targeted therapies reverse TCD8 exhaustion/anergy. However, whether they alter the epitope breadth of TCD8 responses remains unclear. This is an important question because subdominant TCD8 are more likely than immunodominant clones to escape tolerance mechanisms and may contribute to protective anticancer immunity...
November 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28921877/analysis-of-infantile-fibrosarcoma-reveals-extensive-t-cell-responses-within-tumors-implications-for-immunotherapy
#14
Hua Zhu, Song Gu, Minzhi Yin, Min Shi, Chao Xin, Jianmin Zhu, Jing Wang, Siqi Huang, Chenjie Xie, Jing Ma, Ci Pan, Jingyan Tang, Min Xu, Xue-Feng Bai
BACKGROUND: Infantile fibrosarcoma (IFS) is a rare pediatric malignancy with relatively good prognosis, but the risk of progression or recurrence after therapy exists. To understand the immune microenvironment of IFS and determine if immunotherapy is a potential treatment, we analyzed T-cell responses in IFS tumors. PROCEDURE: IFS tumors were analyzed by immunohistochemistry and multicolor flow cytometry to characterize immune cell infiltration and function. Tumor infiltrating lymphocytes (TILs) were expanded in vitro and evaluated for recognition of autologous tumor cells...
September 17, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28882621/antibodies-targeting-btla-or-tim-3-enhance-hiv-1-specific-t-cell-responses-in-combination-with-pd-1-blockade
#15
Katharina Grabmeier-Pfistershammer, Carmen Stecher, Markus Zettl, Sandra Rosskopf, Armin Rieger, Gerhard J Zlabinger, Peter Steinberger
Persistent stimulation with antigens derived from viruses that establish chronic infections or tumour antigens results in the exhaustion of T cells. Coinhibitory receptors like PD-1 and CTLA-4 function as immune checkpoints on exhausted T cells. Blocking these molecules with antibodies improve immunity to cancer cells. Immune checkpoint inhibitors targeting other coinhibitory receptors might have a similar role in improving T cell function and thus also utility in cancer therapy. Using HIV-specific T cells as a model for exhaustion we have evaluated the capacity of antibodies targeting TIM-3, BTLA, CD160, LAG-3 and CTLA-4 alone or in combination with a PD-1 antibody to enhance proliferation and cytokine production in response to Gag and Nef peptides...
September 4, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28875836/coinhibitory-molecule-pd-1-as-a-therapeutic-target-in-the-microenvironment-of-multiple-myeloma
#16
Djordje Atanackovic, Tim Luetkens, Mary Steinbach, Nicolaus Kröger
Immunological dysfunction in the microenvironment of multiple myeloma is a potential target for immune-mediated therapies. The programmed death 1 (PD-1) receptor is expressed on the surface of exhausted T and B cells and its ligand PD-L1 is expressed on tumor cells and inhibits T-cell-mediated apoptosis. Inhibiting such "checkpoint" by monoclonal antibodies recently has been shown high activity in solid tumors and malignant lymphomas. In patients with multiple myeloma PD-L1 is overexpressed on myeloma cells and PD1 on T-cells suggesting an active role of PD- 1/PD-L1 in the immunosuppressive microenvironment...
September 6, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28866656/immune-checkpoint-inhibitors-in-cancer-therapy
#17
Eika S Webb, Peng Liu, Renato Baleeiro, Nicholas R Lemoine, Ming Yuan, Yao-He Wang
In recent years immune checkpoint inhibitors have garnered attention as being one of the most promising types of immunotherapy on the horizon. There has been particular focus on the immune checkpoint molecules, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) which have been shown to have potent immunomodulatory effects through their function as negative regulators of T cell activation. CTLA-4, through engagement with its ligands B7-1 (CD80) and B7-2 (CD86), plays a pivotal role in attenuating the activation of naïve and memory T cells...
September 3, 2017: Journal of Biomedical Research
https://www.readbyqxmd.com/read/28822650/progressive-and-reversible-conduction-disease-with-checkpoint-inhibitors
#18
Neeti Reddy, Rohit Moudgil, Juan C Lopez-Mattei, Kaveh Karimzad, Elie N Mouhayar, Neeta Somaiah, Anthony P Conley, Shreyaskumar Patel, Dana E Giza, Cezar Iliescu
Novel antineoplastic therapies are focused on harnessing our own immune system to fight cancer. To that end, cytotoxic T-lymphocyte-associated antigen 4 and programmed death ligand 1 are 2 coinhibitory signals that play central roles in decreasing T-cell response and represent a class of medications termed "checkpoint inhibitors." We present an unusual case of progressive conduction abnormalities induced by checkpoint inhibitors. Prompt medical intervention resulted in full recovery. Despite the anticancer efficacy, the newer antineoplastic agents pose a significant and often life-threatening risk of cardiotoxicity...
October 2017: Canadian Journal of Cardiology
https://www.readbyqxmd.com/read/28768726/cutting-edge-2b4-mediated-coinhibition-of-cd4-t-cells-underlies-mortality-in-experimental-sepsis
#19
Ching-Wen Chen, Rohit Mittal, Nathan J Klingensmith, Eileen M Burd, Cox Terhorst, Greg S Martin, Craig M Coopersmith, Mandy L Ford
Sepsis is a leading cause of death in the United States, but the mechanisms underlying sepsis-induced immune dysregulation remain poorly understood. 2B4 (CD244, SLAM4) is a cosignaling molecule expressed predominantly on NK cells and memory CD8(+) T cells that has been shown to regulate T cell function in models of viral infection and autoimmunity. In this article, we show that 2B4 signaling mediates sepsis lymphocyte dysfunction and mortality. 2B4 expression is increased on CD4(+) T cells in septic animals and human patients at early time points...
September 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28761757/mechanisms-of-action-and-rationale-for-the-use-of-checkpoint-inhibitors-in-cancer
#20
REVIEW
Clemence Granier, Eleonore De Guillebon, Charlotte Blanc, Helene Roussel, Cecile Badoual, Elia Colin, Antonin Saldmann, Alain Gey, Stephane Oudard, Eric Tartour
The large family of costimulatory molecules plays a crucial role in regulation of the immune response. These molecules modulate TCR signalling via phosphorylation cascades. Some of the coinhibitory members of this family, such as PD-1 and CTLA-4, already constitute approved targets in cancer therapy and, since 2011, have opened a new area of antitumour immunotherapy. Many antibodies targeting other inhibitory receptors (Tim-3, VISTA, Lag-3 and so on) or activating costimulatory molecules (OX40, GITR and so on) are under evaluation...
2017: ESMO Open
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