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https://www.readbyqxmd.com/read/28987965/emerging-targets-in-cancer-immunotherapy
#1
REVIEW
Samantha Burugu, Amanda R Dancsok, Torsten O Nielsen
The first generation of immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1) targeted natural immune homeostasis pathways, co-opted by cancers, to drive anti-tumor immune responses. These agents led to unprecedented results in patients with previously incurable metastatic disease and may become first-line therapies for some advanced cancers. However, these agents are efficacious in only a minority of patients. Newer strategies are becoming available that target additional immunomodulatory mechanisms to activate patients' own anti-tumor immune responses...
October 5, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/28912398/-therapeutic-cancer-vaccine-and-immune-checkpoint-inhibitor
#2
Kousaku Mimura, Koji Kono
Therapeutic cancer vaccine enhances a specific immune response against tumor cells in vivo, resulting in exertion of antitumor effects. On the other hand, immune checkpoint inhibitors promote the induction of tumor-specific T cells and also enhance the cytotoxic abilityof these T cells in tumor microenvironment. There is a possibilitythat immune checkpoint inhibitors enhance tumor immune responses induced bytherapeutic cancer vaccine, and it is expected that additive or synergistic effects will be obtained bythe combination of them...
September 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/28900677/tim-3-lag-3-and-tigit
#3
Nicole Joller, Vijay K Kuchroo
Co-inhibitory receptors play a key role in regulating T cell responses and maintaining immune homeostasis. Their inhibitory function prevents autoimmune responses but also restricts the ability of T cells to mount effective immune responses against tumors or persistent pathogens. T cells express a module of co-inhibitory receptors, which display great diversity in expression, structure, and function. Here, we focus on the co-inhibitory receptors Tim-3, Lag-3, and TIGIT and how they regulate T cell function, maintenance of self-tolerance, their role in regulating ongoing T cell responses at peripheral tissues, and their synergistic effects in regulating autoimmunity and antitumor responses...
September 13, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28893624/cd8-t-cells-expressing-both-pd-1-and-tigit-but-not-cd226-are-dysfunctional-in-acute-myeloid-leukemia-aml-patients
#4
Mengjie Wang, Jin Bu, Maohua Zhou, Jessica Sido, Yu Lin, Guanfang Liu, Qiwen Lin, Xiuzhang Xu, Jianmei W Leavenworth, Erxia Shen
Acute myeloid leukemia (AML) is one of the most common types of leukemia among adults with an overall poor prognosis and very limited treatment management. Immune checkpoint blockade of PD-1 alone or combined with other immune checkpoint blockade has gained impressive results in murine AML models by improving anti-leukemia CD8(+)T cell function, which has greatly promoted the strategy to utilize combined immune checkpoint inhibitors to treat AML patients. However, the expression profiles of these inhibitory receptors in T cells from AML patients have not been clearly defined...
September 8, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28883004/cd155t-tigit-signaling-regulates-cd8-t-cell-metabolism-and-promotes-tumor-progression-in-human-gastric-cancer
#5
Wei-Ling He, Hui Zhang, Fei Han, Xin-Lin Chen, Run Lin, Wei Wang, Hai-Bo Qiu, Zhenhong Zhuang, Qi Liao, Weijing Zhang, Qinbo Cai, Yongmei Cui, Wenting Jiang, Han Wang, Zunfu Ke
The T cell surface molecule TIGIT is an immune checkpoint molecule that inhibits T cell responses, but its roles in cancer are little understood. In this study, we evaluated the role TIGIT checkpoint plays in the development and progression of gastric cancer (GC). We show that the percentage of CD8 T cells that are TIGIT+ was increased in GC patients compared to healthy individuals. These cells showed functional exhaustion with impaired activation, proliferation, cytokine production and metabolism, all of which were rescued by glucose...
September 7, 2017: Cancer Research
https://www.readbyqxmd.com/read/28870470/poliovirus-receptor-more-than-a-simple-viral-receptor
#6
REVIEW
Jonathan R Bowers, James M Readler, Priyanka Sharma, Katherine J D A Excoffon
The human poliovirus receptor (PVR) is a cell surface protein with a multitude of functions in human biology. PVR was initially identified as the receptor for the human poliovirus and recent discoveries have given a greater insight into both its morphology and its function. Alternative splicing of the PVR gene results in a total of 4 alternatively spliced isoforms. Two of these isoforms lack a complete transmembrane domain and are considered soluble and block viral infection; the remaining two transmembrane isoforms differ only at their extreme C-terminal domains resulting in differential localization in epithelia and polarity of viral infection...
September 7, 2017: Virus Research
https://www.readbyqxmd.com/read/28865357/check-point-inhibitors-as-therapies-for-infectious-diseases
#7
REVIEW
Maureen A Cox, Robert Nechanitzky, Tak W Mak
The recent successes of immune check point targeting therapies in treating cancer patients has driven a resurgence of interest in targeting these pathways in chronically infected patients. While still in early stages, basic and clinical data suggest that blockade of CTLA-4 and PD-1 can be beneficial in the treatment of chronic HIV, HBV, and HCV infection, as well as other chronic maladies. Furthermore, novel inhibitory receptors such as Tim-3, LAG-3, and TIGIT are the potential next wave of check points that can be manipulated for the treatment of chronic infection...
August 30, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28844471/remodeling-t-cell-compartments-during-anti-cd3-immunotherapy-of-type-1-diabetes
#8
RANDOMIZED CONTROLLED TRIAL
S Alice Long, Jerill Thorpe, Kevan C Herold, Mario Ehlers, Srinath Sanda, Noha Lim, Peter S Linsley, Gerald T Nepom, Kristina M Harris
The immunological mechanism(s) of action whereby teplizumab preserves C-peptide levels in the progression of patients with recent onset type 1 diabetes (T1D) is still not well understood. In the present study, we evaluated the kinetics of T cell modulation in peripheral blood following two 14-day courses of teplizumab therapy one year apart in recent onset T1D participants in the AbATE clinical trial. Transient rises in PD-1+Foxp3+ Treg and potentially anergic (CD57-KLRG1-PD-1+) cells in the circulating CD4 T cell compartment were paralleled by more profound increases in circulating CD8 T cells with traits of exhaustion (CD57-KLRG1+PD-1+, TIGIT+KLRG1+, and persistent down-modulation of CD127)...
September 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28791012/extracellular-vesicles-transfer-the-receptor-programmed-death-1-in-rheumatoid-arthritis
#9
Stinne R Greisen, Yan Yan, Aida S Hansen, Morten T Venø, Jens R Nyengaard, Søren K Moestrup, Malene Hvid, Gordon J Freeman, Jørgen Kjems, Bent Deleuran
INTRODUCTION: Extracellular vesicles (EVs) have been recognized as route of communication in the microenvironment. They transfer proteins and microRNAs (miRNAs) between cells, and possess immunoregulatory properties. However, their role in immune-mediated diseases remains to be elucidated. We hypothesized a role for EVs in the rheumatoid arthritis (RA) joint, potentially involving the development of T cell exhaustion and transfer of the co-inhibitory receptor programmed death 1 (PD-1)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28664195/partial-exhaustion-of-cd8-t-cells-and-clinical-response-to-teplizumab-in-new-onset-type-1-diabetes
#10
S Alice Long, Jerill Thorpe, Hannah A DeBerg, Vivian Gersuk, James Eddy, Kristina M Harris, Mario Ehlers, Kevan C Herold, Gerald T Nepom, Peter S Linsley
Biologic treatment of T1D typically results in transient stabilization of C-peptide levels (a surrogate for endogenous insulin secretion) in some patients, followed by progression at the same rate as in untreated control groups. Here, we used integrated systems biology and flow cytometry approaches with clinical trial blood samples to elucidate pathways associated with C-peptide stabilization in T1D subjects treated with the anti-CD3 monoclonal antibody teplizumab. We identified a population of CD8 T cells that accumulated in subjects with the best response to treatment (responders) and showed that these cells phenotypically resembled exhausted T cells by expressing high levels of the transcription factor EOMES, effector molecules, and multiple inhibitory receptors (IRs), including TIGIT and KLRG1...
November 2016: Science Immunology
https://www.readbyqxmd.com/read/28652380/immune-escape-in-breast-cancer-during-in-situ-to-invasive-carcinoma-transition
#11
Carlos R Gil Del Alcazar, Sung Jin Huh, Muhammad B Ekram, Anne Trinh, Lin L Liu, Francisco Beca, Xiaoyuan Zi, Minsuk Kwak, Helga Bergholtz, Ying Su, Lina Ding, Hege G Russnes, Andrea L Richardson, Kirsten Babski, Elizabeth Min Hui Kim, Charles H McDonnell, Jon Wagner, Ron Rowberry, Gordon J Freeman, Deborah Dillon, Therese Sorlie, Lisa M Coussens, Judy E Garber, Rong Fan, Kristie Bobolis, D Craig Allred, Joon Jeong, So Yeon Park, Franziska Michor, Kornelia Polyak
To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45(+)CD3(+) T cells demonstrated a decrease in CD8(+) signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB(+)CD8(+) T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC...
October 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28629373/blimp-1-impairs-t-cell-function-via-upregulation-of-tigit-and-pd-1-in-patients-with-acute-myeloid-leukemia
#12
Liuluan Zhu, Yaxian Kong, Jianhong Zhang, David F Claxton, W Christopher Ehmann, Witold B Rybka, Neil D Palmisiano, Ming Wang, Bei Jia, Michael Bayerl, Todd D Schell, Raymond J Hohl, Hui Zeng, Hong Zheng
BACKGROUND: T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional regulation of TIGIT and PD-1 in AML...
June 19, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28623459/blockade-of-cd112r-and-tigit-signaling-sensitizes-human-natural-killer-cell-functions
#13
Feng Xu, Alexander Sunderland, Yue Zhou, Richard D Schulick, Barish H Edil, Yuwen Zhu
Trastuzumab is the first-line drug to treat breast cancer with high Her2 expression. However, many cancers failed to respond, largely due to their resistance to NK cell-triggered antibody-dependent cellular cytotoxicity (ADCC). Poliovirus receptor (PVR)-like molecules are known to be important for lymphocyte functions. We found that all PVR-like receptors are expressed on human NK cells, and only TIGIT is preferentially expressed on the CD16+ NK cell subset. Disrupting the interactions of PVR-like receptors with their ligands on cancer cells regulates NK cell activity...
June 16, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28620836/sox2-immunity-and-tissue-resident-memory-in-children-and-young-adults-with-glioma
#14
Juan C Vasquez, Anita Huttner, Lin Zhang, Asher Marks, Amy Chan, Joachim M Baehring, Kristopher T Kahle, Kavita M Dhodapkar
Therapies targeting immune checkpoints are effective in tumors with a high mutation burden that express multiple neo-antigens. However, glial tumors including those seen in children carry fewer mutations and there is an unmet need to identify new antigenic targets of anti-tumor immunity. SOX2 is an embryonal stem cell antigen implicated in the biology of glioma initiating cells. Expression of SOX2 by pediatric glial tumors and the capacity of the immune system in these patients to recognize SOX2 has not been previously studied...
August 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28612942/cytomegalovirus-vector-expressing-rae-1%C3%AE-induces-enhanced-anti-tumor-capacity-of-murine-cd8-t-cells
#15
Tihana Tršan, Kristina Vuković, Petra Filipović, Ana Lesac Brizić, Niels A W Lemmermann, Kilian Schober, Dirk H Busch, William J Britt, Martin Messerle, Astrid Krmpotić, Stipan Jonjić
Designing CD8(+) T-cell vaccines, which would provide protection against tumors is still considered a great challenge in immunotherapy. Here we show the robust potential of cytomegalovirus (CMV) vector expressing the NKG2D ligand RAE-1γ as CD8(+) T cell-based vaccine against malignant tumors. Immunization with the CMV vector expressing RAE-1γ, delayed tumor growth or even provided complete protection against tumor challenge in both prophylactic and therapeutic settings. Moreover, a potent tumor control in mice vaccinated with this vector can be further enhanced by blocking the immune checkpoints TIGIT and PD-1...
June 14, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28610918/cd155-blockade-improves-survival-in-experimental-sepsis-by-reversing-dendritic-cell-dysfunction
#16
Yan Meng, Zhenzhen Zhao, Wenzhong Zhu, Tao Yang, Xiaoming Deng, Rui Bao
Immunosuppression is involved in septic processes, and results in an inability to eradicate the primary infection as well as a propensity to acquire secondary infections. In the present study, we found that the expression of CD155 on dendritic cells (DCs) and TIGIT on T cells were strikingly increased in septic mice. Furthermore, anti-CD155 antibody treatment could improve survival rate in mouse sepsis models through deceasing bacterial burden in both blood and peritoneal lavage fluid. Meanwhile, CD155 blockade efficiently increased the expression of TNF-a, IL-6 and decreased the level of IL-10 in blood and peritoneal lavage fluid of septic mice...
August 19, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28588576/pd-1-blockade-promotes-emerging-checkpoint-inhibitors-in-enhancing-t-cell-responses-to-allogeneic-dendritic-cells
#17
Carmen Stecher, Claire Battin, Judith Leitner, Markus Zettl, Katharina Grabmeier-Pfistershammer, Christoph Höller, Gerhard J Zlabinger, Peter Steinberger
Immune checkpoint inhibitors, which target coinhibitory T cell molecules to promote anticancer immune responses, are on the rise to become a new pillar of cancer therapy. However, current immune checkpoint-based therapies are successful only in a subset of patients and acquired resistances pose additional challenges. Finding new targets and combining checkpoint inhibitors might help to overcome these limitations. In this study, human T cells stimulated with allogeneic dendritic cells (DCs) were used to compare immune checkpoint inhibitors targeting TIM-3, BTLA, LAG-3, CTLA-4, and TIGIT alone or in combination with a PD-1 antibody...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28567438/in-depth-immunophenotyping-data-of-il-6r-on-the-human-peripheral-regulatory-t-cell-treg-compartment
#18
Ricardo C Ferreira, Daniel B Rainbow, Arcadio Rubio García, Marcin L Pekalski, Linsey Porter, João J Oliveira, Frank Waldron-Lynch, Linda S Wicker, John A Todd
We provide in this paper a detailed characterization of the human peripheral CD4(+) CD127(low)CD25(+) regulatory T cell (Treg) compartment, with a particular emphasis in defining the population expressing higher levels of the IL-6 receptor (IL-6R). We provide a description of the phenotype of this population by assessing both the surface expression by flow cytometry as well as their transcriptional profile and functional features. In addition, we also present functional data describing the responsiveness of these subsets to IL-6 signalling in vitro and to IL-2 in vivo...
June 2017: Data in Brief
https://www.readbyqxmd.com/read/28525897/a-cellular-platform-for-the-evaluation-of-immune-checkpoint-molecules
#19
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...
May 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28515320/recognition-of-nectin-2-by-the-natural-killer-cell-receptor-t-cell-immunoglobulin-and-itim-domain-tigit
#20
Felix A Deuss, Benjamin S Gully, Jamie Rossjohn, Richard Berry
T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on the surface of natural killer (NK) cells. TIGIT recognizes nectin and nectin-like adhesion molecules and thus plays a critical role in the innate immune response to malignant transformation. Although the TIGIT nectin-like protein-5 (necl-5) interaction is well understood, how TIGIT engages nectin-2, a receptor that is broadly over-expressed in breast and ovarian cancer, remains unknown. Here, we show that TIGIT bound to the immunoglobulin domain of nectin-2 that is most distal from the membrane with an affinity of 6 μm, which was moderately lower than the affinity observed for the TIGIT/necl-5 interaction (3...
July 7, 2017: Journal of Biological Chemistry
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