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T cell inhibitory pathway

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https://www.readbyqxmd.com/read/29330145/mbd2-ablation-impairs-lymphopoiesis-and-impedes-progression-and-maintenance-of-t-all
#1
Mi Zhou, Kuangguo Zhou, Ling Cheng, Xing Chen, Jue Wang, Xiao-Min Wang, Yingchi Zhang, Qilin Yu, Shu Zhang, Di Wang, Liang Huang, Mei Huang, Ding Ma, Tao Cheng, Cong-Yi Wang, Weiping Yuan, Jianfeng Zhou
Aberrant DNA methylation patterns in leukemia might be exploited for therapeutic targeting. In this study, we employed a genetically deficient mouse model to explore the role of the methylated DNA binding protein MBD2 in normal and malignant hematopoiesis. MBD2 ablation led to diminished lymphocytes. Functional defects of the lymphoid compartment were also observed after in vivo reconstitution of MBD2-deficient hematopoietic stem cells (HSC). In an established model of Notch1-driven T cell acute lymphoblastic leukemia (T-ALL), MBD2 ablation impeded malignant progression and maintenance by attenuating the Wnt signaling pathway...
January 12, 2018: Cancer Research
https://www.readbyqxmd.com/read/29324844/absence-of-myeloid-klf4-reduces-prostate-cancer-growth-with-pro-atherosclerotic-activation-of-tumor-myeloid-cells-and-infiltration-of-cd8-t-cells
#2
David J Barakat, Rahul Suresh, Theresa Barberi, Kenneth J Pienta, Brian W Simons, Alan D Friedman
The microenvironment of prostate cancer often includes abundant tumor-associated macrophages (TAMs), with their acquisition of an M2 phenotype correlating with local aggressiveness and metastasis. Tumor-derived M-CSF contributes to TAM M2 polarization, and M-CSF receptor inhibition slows prostate cancer growth in model systems. As additional cytokines can direct TAM M2 polarization, targeting downstream transcription factors could avoid resistance. Klf4 and C/EBPβ each contribute to monocyte development, and reduced expression of macrophage Klf4 or C/EBPβ favors their adoption of a pro-inflammatory M1 state...
2018: PloS One
https://www.readbyqxmd.com/read/29318591/immune-checkpoint-molecules-in-acute-myeloid-leukaemia-managing-the-double-edged-sword
#3
REVIEW
Willemijn Hobo, Tim J A Hutten, Nicolaas P M Schaap, Harry Dolstra
New immunotherapeutic interventions have revolutionized cancer treatment. The immune responsiveness of acute myeloid leukaemia (AML) was first demonstrated by allogeneic stem cell transplantation. In addition, milder immunotherapeutic approaches are exploited. However, the long-term efficacy of these therapies is hampered by various immune resistance and editing mechanisms. In this regard, co-inhibitory signalling pathways have been shown to play a crucial role. Via up-regulation of inhibitory checkpoints, tumour-reactive T cell and Natural Killer cell responses can be strongly impeded...
January 9, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29311234/mycoplasma-bovis-induced-inhibition-of-bovine-pbmc-proliferation-is-ameliorated-after-blocking-the-immune-inhibitory-programmed-death-1-pd-1-receptor
#4
Muhammad Suleman, Farhan S Cyprian, Steve Jimbo, Teresia Maina, Tracy Prysliak, Claire Windeyer, Jose Perez-Casal
Mycoplasma bovis (M. bovis) induced-immune suppression is a major obstacle faced by the host for controlling infections. M. bovis impairment of antigen-specific T-cells responses is achieved through inhibiting the proliferation of peripheral-blood mononuclear cells (PBMC). This impairment may contribute to the persistence of M. bovis infection in various sites including lungs and its systemic spread to various organs like joints, with the underlying mechanisms remaining elusive. Here, we elucidated the role of the immune-inhibitory receptor programmed death-1 (PD-1) and its ligand (PD-L1) in M...
January 8, 2018: Infection and Immunity
https://www.readbyqxmd.com/read/29305519/antigen-specific-antitumor-responses-induced-by-ox40-agonist-are-enhanced-by-ido-inhibitor-indoximod
#5
Zuzana Berrong, Mikayel Mkrtichyan, Shamim Ahmad, Mason Webb, Eslam Mohamed, Grigori Okoev, Adelaida Matevosyan, Rajeev Shrimali, Rasha Abu Eid, Scott Hammond, John E Janik, Samir N Khleif
Although an immune response to tumors may be generated using vaccines, so far, this approach has only shown minimal clinical success. This is attributed to the tendency of cancer to escape immune surveillance via multiple immune suppressive mechanisms. Successful cancer immunotherapy requires targeting these inhibitory mechanisms along with enhancement of antigen-specific immune responses to promote sustained tumor-specific immunity. Here we evaluated the effect of indoximod, an inhibitor of the immunosuppressive indoleamine-(2,3)-dioxygenase (IDO) pathway, on antitumor efficacy of anti-OX40 agonist in the context of vaccine in the IDO- TC-1 tumor model...
January 5, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29296975/cell-surface-c-type-lectin-like-receptor-clec-1-dampens-dendritic-cell-activation-and-downstream-th17-responses
#6
Maria Dolores Lopez Robles, Annaick Pallier, Virginie Huchet, Laetitia Le Texier, Severine Remy, Cecile Braudeau, Laurence Delbos, Aurelie Moreau, Cedric Louvet, Carole Brosseau, Pierre-Joseph Royer, Antoine Magnan, Franck Halary, Regis Josien, Maria-Cristina Cuturi, Ignacio Anegon, Elise Chiffoleau
Dendritic cells (DCs) represent essential antigen-presenting cells that are critical for linking innate and adaptive immunity, and influencing T-cell responses. Among pattern recognition receptors, DCs express C-type lectin receptors triggered by both exogenous and endogenous ligands, therefore dictating pathogen response, and also shaping T-cell immunity. We previously described in rat, the expression of the orphan C-type lectin-like receptor-1 (CLEC-1) by DCs and demonstrated in vitro its inhibitory role in downstream T helper 17 (Th17) activation...
March 28, 2017: Blood Advances
https://www.readbyqxmd.com/read/29286158/metformin-inhibits-hacat-cell-viability-via-the-mir-21-pten-akt-signaling-pathway
#7
Yue Deng, Weiyuan Ma
Substantial preclinical evidence has indicated out a direct anti‑proliferation effect of metformin on various solid tumors; however, further and more detailed exploration into its molecular mechanism remains to be performed. The present study aimed to investigate the effect of metformin on cell viability and its underlying mechanism, in the cultured human skin keratinocyte cell line, HaCaT. In addition, it aimed to clarify the role of the microRNA-21(miR-21)/phosphatase and tensin homolog (PTEN)/AKT serine/threonine kinase 1 (Akt) signaling pathway, which has been hypothesized to be involved in the molecular mechanism of this drug...
December 27, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29282694/immune-checkpoint-blockade-in-breast-cancer-therapy
#8
Xia Bu, Yihui Yao, Xiaoyu Li
Cancer immunotherapy is emerging as the most promising novel strategy for cancer treatment. Cancer immunotherapy is broadly categorized into three forms: immune checkpoint modulation, adoptive cell transfer, and cancer vaccine. Immune checkpoint blockade is demonstrated as the most clinically effective treatment with low immune-related adverse events (irAE). Blockade of PD-1/PD-L1 and CTLA-4 has achieved remarkable success in treating various types of tumors, which sparks great interests in this therapeutic strategy and expands the role of immune checkpoint blockade in treating tumors including breast cancer...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29282323/affinity-purification-mass-spectrometry-analysis-of-pd-1-uncovers-sap-as-a-new-checkpoint-inhibitor
#9
Michael Peled, Anna S Tocheva, Sabina Sandigursky, Shruti Nayak, Elliot A Philips, Kim E Nichols, Marianne Strazza, Inbar Azoulay-Alfaguter, Manor Askenazi, Benjamin G Neel, Adam J Pelzek, Beatrix Ueberheide, Adam Mor
Programmed cell death-1 (PD-1) is an essential inhibitory receptor in T cells. Antibodies targeting PD-1 elicit durable clinical responses in patients with multiple tumor indications. Nevertheless, a significant proportion of patients do not respond to anti-PD-1 treatment, and a better understanding of the signaling pathways downstream of PD-1 could provide biomarkers for those whose tumors respond and new therapeutic approaches for those whose tumors do not. We used affinity purification mass spectrometry to uncover multiple proteins associated with PD-1...
December 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29282318/src1-promotes-th17-differentiation-by-overriding-foxp3-suppression-to-stimulate-ror%C3%AE-t-activity-in-a-pkc-%C3%AE-dependent-manner
#10
Subha Sen, Fei Wang, Jing Zhang, Zhiheng He, Jian Ma, Yousang Gwack, Jianming Xu, Zuoming Sun
Th17 cells are major players in multiple autoimmune diseases and are developmentally contingent on reciprocal functionality between the transcription factor Retineic acid receptor-related orphan nuclear receptor gamma (RORγt) and Forkhead box protein P3 (Foxp3). Here we deciphered a previously unappreciated role of Steroid receptor coactivator 1 (SRC1) in defining the lineage decision for the development of Th17 versus induced T-regulatory (iTreg) cells. We demonstrate that SRC1 functions as a critical coactivator for RORγt in vivo to promote the functional dominance of RORγt over Foxp3 and thus establishing an unopposed Th17 differentiation program...
December 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29275462/cancer-immunotherapy-targets-based-on-understanding-the-t-cell-inflamed-versus-non-t-cell-inflamed-tumor-microenvironment
#11
Thomas F Gajewski, Leticia Corrales, Jason Williams, Brendan Horton, Ayelet Sivan, Stefani Spranger
Most cancers express tumor antigens that can be recognized by T cells of the host. The fact that cancers become clinically evident nonetheless implies that immune escape must occur. Two major subsets of human melanoma metastases have been identified based on gene expression profiling. One subgroup has a T cell-inflamed phenotype that includes expression of chemokines, T cell markers, and a type I IFN signature. In contrast, the other major subset lacks this phenotype and has been designated as non-T cell-inflamed...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29259959/fexaramine-inhibits-receptor-activator-of-nuclear-factor-%C3%AE%C2%BAb-ligand-induced-osteoclast-formation-via-nuclear-factor-of-activated-t-cells-signaling-pathways
#12
Ting Zheng, Na-Young Kim, Mijung Yim
Background: Osteoclasts are bone resorbing cells and are responsible for bone erosion in diseases as diverse as osteoporosis, periodontitis, and rheumatoid arthritis. Fexaramine has been developed as an agonist for the farnesoid X receptor (FXR). This study investigated the effects of fexaramine on receptor activator of nuclear factor (NF)-κB ligand (RANKL)-induced osteoclast formation and signaling pathways. Methods: Osteoclasts were formed by culturing mouse bone marrow-derived macrophages (BMMs) with macrophage colony-stimulating factor (M-CSF) and RANKL...
November 2017: Journal of Bone Metabolism
https://www.readbyqxmd.com/read/29246400/immunomodulatory-effects-of-myeloid-derived-suppressor-cells-in-diseases-role-in-cancer-and-infections
#13
REVIEW
Ruth S E Tamadaho, Achim Hoerauf, Laura E Layland
Myeloid-derived suppressor cells (MDSCs) are heterogeneous cells capable of abrogating T and B cells responses and have been identified in numerous cancers. As with other regulatory cell populations, they aim to maintain balance between host-defence-associated inflammation and ensuing tissue pathology. MDSC accumulation and/or activation involve several growth factors and cytokines including Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) and Interleukin (IL)-6 and suppression has been linked to receptors such as IL-4Rα...
July 4, 2017: Immunobiology
https://www.readbyqxmd.com/read/29239817/in-vitro-and-in-vivo-antitumor-effects-of-the-diterpene-enriched-extract-from-taxodium-ascendens-through-the-mitochondrial-dependent-apoptosis-pathway
#14
Jie Yang, Chan Xu, Hao Chen, Mi Huang, Xinhua Ma, Shihao Deng, Yun Huang, Yanzhang Wen, Xinzhou Yang, Ping Song
Extracts and components of Taxodium ascendens Brongn, an excellent afforestation tree, have exhibited several activities, including antibacterial activity and inhibitory activity on carbonic anhydrase II. However, the anti-hepatocellular carcinoma (anti-HCC) activity of extracts from the leaves of T. ascendens (TALE) remains unclear. In the present study, six diterpenoid compounds were isolated from a TALE extract. Here, the pro-apoptotic activities and the molecular mechanisms of TALE and the compounds 1-6 on HepG2 and Hep3B HCC cells were evaluated...
November 24, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29238207/advances-in-t-cell-checkpoint-immunotherapy-for-head-and-neck-squamous-cell-carcinoma
#15
REVIEW
Xinmeng Qi, Bo Jia, Xue Zhao, Dan Yu
Head and neck squamous cell carcinoma (HNSCC) has been found to be a complex group of malignancies characterized by their profound immunosuppression and high aggressiveness. In most cases of advanced HNSCC, treatment fails to obtain total cancer cure. Efforts are needed to develop new therapeutic approaches to improve HNSCC outcomes. In this light, T-cells "immune checkpoint" has attracted much attention in cancer immunotherapy. It has been broadly accepted that inhibitory T-cell immune checkpoints contribute to tumor immune escape through negative immune regulatory signals (cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4], programmed cell death 1 [PD-1], B7-H3, and B7-H4, etc)...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29238163/the-coexpression-of-multi-immune-inhibitory-receptors-on-t-lymphocytes-in-primary-non-small-cell-lung-cancer
#16
REVIEW
Wenjie Guo, Sihan Liu, Xiaoli Zhang, Yating Chen, Ruolan Qian, Ziyuan Zou, Xin Chen, Peng Luo
Non-small-cell lung cancer (NSCLC) is a common disease threatening the health of humankind. It has a low survival rate and a poor prognosis. Under normal circumstances, tumor infiltrating lymphocytes (TILs) play the main role in the antitumor process, but studies in recent years have found that NSCLC is capable of releasing various immunosuppressive factors, inducing the TILs to exhibit high expression of immune inhibitory receptors and relevant immunosuppressive factors. They can not only activate their own signal pathways but also block those of TILs, which causes inefficiency of tumor destruction...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29228684/atorvastatin-downregulates-co-inhibitory-receptor-expression-by-targeting-ras-activated-mtor-signalling
#17
Isobel Okoye, Afshin Namdar, Lai Xu, Nicole Crux, Shokrollah Elahi
Regulation of T cell function in the steady state is mediated by co-inhibitory receptors or immune checkpoints such as PD-1, CTLA-4, TIM-3 and LAG-3. Persistent antigen stimulation, during chronic viral infections and cancer, results in sustained expression of multiple co-inhibitory receptors and subsequently poor effector T cell function. Immune checkpoint blockade using monoclonal antibodies against PD-1, PDL-1 and CTLA-4 has been implemented as an immunotherapy strategy- resulting in restoration of T cell function and reduction of viral load or tumour growth...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29228681/cyclophosphamide-causes-osteoporosis-in-c57bl-6-male-mice-suppressive-effects-of-cyclophosphamide-on-osteoblastogenesis-and-osteoclastogenesis
#18
Dongfeng Zhao, Chenglong Wang, Yongjian Zhao, Bing Shu, Youji Jia, Shufen Liu, Hongshen Wang, Junli Chang, Weiwei Dai, Sheng Lu, Qi Shi, Yanping Yang, Yan Zhang, Yongjun Wang
The clinical evidence indicated that cyclophosphamide (CPD), one of the chemotherapy drugs, caused severe deteriorations in bones of cancer patients. However, the exact mechanisms by which CPD exerts effects on bone remodeling is not yet fully elucidated. Therefore, this study was performed to investigate the role and potential mechanism of CPD in osteoblastogenesis and osteoclastogenesis. Here it was found that CPD treatment (100mg/kg/day) for 7 days led to osteoporosis phenotype in male mice. CPD inhibited osteoblastogenesis as shown by decreasing the number and differentiation of bone mesenchymal stem cells (MSCs) and reducing the formation and activity of osteoblasts...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29228614/dual-effects-of-radiation-bystander-signaling-in-urothelial-cancer-purinergic-activation-of-apoptosis-attenuates-survival-of-urothelial-cancer-and-normal-urothelial-cells
#19
Malgorzata A Bill, Kirtiman Srivastava, Conor Breen, Karl T Butterworth, Stephen J McMahon, Kevin M Prise, Karen D McCloskey
Radiation therapy (RT) delivers tumour kill, directly and often via bystander mechanisms. Bladder toxicity is a dose limiting constraint in pelvic RT, manifested as radiation cystitis and urinary symptoms. We aimed to investigate the impact of radiation-induced bystander signaling on normal/cancer urothelial cells. Human urothelial cancer cells T24, HT1376 and normal urothelial cells HUC, SV-HUC were used. Cells were irradiated and studied directly, or conditioned medium from irradiated cells (CM) was transferred to naïve, cells...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29225597/tregs-where-we-are-and-what-comes-next
#20
REVIEW
Hai Zhao, Xuelian Liao, Yan Kang
Regulatory T cells are usually recognized as a specialized subset of CD4+ T cells functioning in establishment and maintenance of immune tolerance. Meanwhile, there is emerging evidence that regulatory T cells (Tregs) are also present in various non-lymphoid tissues, and that they have unique phenotypes credited with activities distinct from regulatory function. Their development and function have been described in plenty of manuscripts in the past two decades. However, with the deepening of research in recent years, emerging evidence revealed some novel mechanisms about how Tregs exert their activities...
2017: Frontiers in Immunology
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