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PD-L1 epigenetic regulation

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https://www.readbyqxmd.com/read/29453977/amelioration-of-progressive-autoimmune-encephalomyelitis-by-epigenetic-regulation-involves-selective-repression-of-mature-neutrophils-during-the-preclinical-phase
#1
Arathi Jayaraman, Monica Sharma, Bellur Prabhakar, Mark Holterman, Sundararajan Jayaraman
We have recently demonstrated that treatment of NOD mice with the epigenetic drug Trichostatin A (TSA) ameliorated myelin peptide induced progressive experimental autoimmune encephalomyelitis (P-EAE). Protection was accompanied by induction of antigen-specific T-cell tolerance in the periphery and reduced the influx of T cells into the spinal cord. In this investigation, we examined whether the epigenetic drug could impact the innate immune system as well. Whereas the mature (MHC class II + ) CD11b + Ly-6G + neutrophils expanded substantially in the peripheral lymphoid compartment during the preclinical phase, the MHC class II + , CD11b + Ly-6C + mature monocytes increased modestly throughout the disease course...
February 14, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29396294/pd-1-pdcd1-promoter-methylation-is-a-prognostic-factor-in-patients-with-diffuse-lower-grade-gliomas-harboring-isocitrate-dehydrogenase-idh-mutations
#2
Lea Kristin Röver, Heidrun Gevensleben, Jörn Dietrich, Friedrich Bootz, Jennifer Landsberg, Diane Goltz, Dimo Dietrich
Immune checkpoints are important targets for immunotherapies. However, knowledge on the epigenetic modification of immune checkpoint genes is sparse. In the present study, we investigated promoter methylation of CTLA4, PD-L1, PD-L2, and PD-1 in diffuse lower-grade gliomas (LGG) harboring isocitrate dehydrogenase (IDH) mutations with regard to mRNA expression levels, clinicopathological parameters, previously established methylation subtypes, immune cell infiltrates, and survival in a cohort of 419 patients with IDH-mutated LGG provided by The Cancer Genome Atlas...
January 24, 2018: EBioMedicine
https://www.readbyqxmd.com/read/29371976/hdac-inhibition-potentiates-immunotherapy-in-triple-negative-breast-cancer
#3
Manuela Terranova-Barberio, Scott Thomas, Niwa Ali, Nela Pawlowska, Jeenah Park, Gregor Krings, Michael D Rosenblum, Alfredo Budillon, Pamela N Munster
Triple-negative breast cancer (TNBC) represents a more aggressive and difficult subtype of breast cancer where responses to chemotherapy occur, but toxicity is significant and resistance often follows. Immunotherapy has shown promising results in various types of cancer, including breast cancer. Here, we investigated a new combination strategy where histone deacetylase inhibitors (HDACi) are applied with immune checkpoint inhibitors to improve immunotherapy responses in TNBC. Testing different epigenetic modifiers, we focused on the mechanisms underlying HDACi as priming modulators of immunotherapy...
December 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/29299180/regulation-of-pd-1-pd-l1-pathway-and-resistance-to-pd-1-pd-l1-blockade
#4
REVIEW
Jie Bai, Zhitao Gao, Xiang Li, Liang Dong, Weidong Han, Jing Nie
Immune checkpoint blockades, such as inhibitors against programmed death 1 (PD-1) and its ligand (PD-L1), have received extensive attention in the past decade because of their dramatic clinical outcomes in advanced malignancies. However, both primary and acquired resistance becomes one of the major obstacles, which greatly limits the long-lasting effects and wide application of PD-1/PD-L1 blockade therapy. PD-1/PD-L1 both regulates and is regulated by cellular signaling pathways and epigenetic modification, thus inhibiting the proliferation and effector function of T and B cells...
December 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/29174371/cooperativity-of-hoxa5-and-stat3-is-critical-for-hdac8-inhibition-mediated-transcriptional-activation-of-pd-l1-in-human-melanoma-cells
#5
Yu Fang Wang, Fen Liu, Simonne Sherwin, Margaret Farrelly, Xu Guang Yan, Amanda Croft, Tao Liu, Lei Jin, Xu Dong Zhang, Chen Chen Jiang
While the expression of programmed death-ligand 1 (PD-L1) is an important mechanism by which cancer cells evade the immune system, PD-L1 expression in cancer cells are commonly associated with patients' responses to treatment with anti-PD-1/PD-L1 antibodies. However, how PD-L1 expression is regulated in melanoma cells remains to be fully elucidated. Here we report that the class I histone deacetylase (HDAC) HDAC8 controls transcriptional activation of PD-L1 by a transcription complex consisting of transcription factors homeobox A5 (HOXA5) and signal transducer and activator of transcription 3 (STAT3)...
November 22, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29124315/the-class-i-iv-hdac-inhibitor-mocetinostat-increases-tumor-antigen-presentation-decreases-immune-suppressive-cell-types-and-augments-checkpoint-inhibitor-therapy
#6
David Briere, Niranjan Sudhakar, David M Woods, Jill Hallin, Lars D Engstrom, Ruth Aranda, Harrah Chiang, Andressa L Sodré, Peter Olson, Jeffrey S Weber, James G Christensen
Checkpoint inhibitor therapy has led to major treatment advances for several cancers including non-small cell lung cancer (NSCLC). Despite this, a significant percentage of patients do not respond or develop resistance. Potential mechanisms of resistance include lack of expression of programmed death ligand 1 (PD-L1), decreased capacity to present tumor antigens, and the presence of an immunosuppressive tumor microenvironment. Mocetinostat is a spectrum-selective inhibitor of class I/IV histone deacetylases (HDACs), a family of proteins implicated in epigenetic silencing of immune regulatory genes in tumor and immune cells...
November 9, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29106445/a-potent-hydroxamic-acid-based-small-molecule-inhibitor-a452-preferentially-inhibits-hdac6-activity-and-induces-cytotoxicity-toward-cancer-cells-irrespective-of-p53-status
#7
Hyun-Wook Ryu, Dong-Hee Shin, Dong Hoon Lee, Hye-Rim Won, So Hee Kwon
HDAC6-selective inhibitors are novel epigenetic anticancer agents. However, their precise mechanisms of action are incompletely understood. We investigated the anticancer mechanisms of the novel potent and selective HDAC6 inhibitor A452 compared with current clinically tested HDAC6 inhibitor ACY-1215. We demonstrate that A452 effectively inhibits the cell growth and viability of various cancer cell types, irrespective of p53 status. A452 induced apoptosis as evidenced by activated caspase 3 and PARP, increased Bak and Bax, and decreased Bcl-xL...
November 2, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29048660/canonical-and-non-canonical-wnt-signaling-in-cancer-stem-cells-and-their-niches-cellular-heterogeneity-omics-reprogramming-targeted-therapy-and-tumor-plasticity-review
#8
Masaru Katoh
Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49)...
November 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28978842/molecular-pathogenesis-and-its-therapeutic-implication-for-atl
#9
Kenji Ishitsuka
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-1). HTLV-1 related proteins Tax and HTLV-1 bZIP factor induce immortalization and transformation of HTLV-1-infected T-lymphocytes and eventually induce clonal proliferation. One of the apparent molecular features in ATL cells is abundant genomic abnormalities targeting characteristic pathways, including T-cell receptor signaling and the NF-κB pathway, G-protein coupled-receptor, including CCR4, and transcriptional regulation...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28939082/epigenetic-therapy-regulates-the-expression-of-aldh1-and-immunologic-response-relevance-to-the-prognosis-of-oral-cancer
#10
Ming-Shao Tsai, Wen-Cheng Chen, Chia-Hsuan Lai, Yu-Yen Chen, Miao-Fen Chen
OBJECTIVES: Aldehyde dehydrogenase 1 (ALDH1) is associated with tumorigenesis, and shown to identify cancer stem cells (CSC)-like cells. We aimed to investigate the significance of ALDH1 in oral squamous cell carcinoma (OSCC) and its correlation with DNMT3b and immune evasion in the present study. METHODS: We retrospectively analyzed the clinical outcomes of OSCC patients and examined its correlation with the levels of ALDH1 in tumors and circulating myeloid-derived suppressor cells (MDSCs) in the peripheral blood...
October 2017: Oral Oncology
https://www.readbyqxmd.com/read/28423491/the-mir-25-93-106b-cluster-regulates-tumor-metastasis-and-immune-evasion-via-modulation-of-cxcl12-and-pd-l1
#11
Michele Cioffi, Sara M Trabulo, Mireia Vallespinos, Deepak Raj, Tony Bou Kheir, Meng-Lay Lin, Julfa Begum, Ann-Marie Baker, Ala Amgheib, Jaimy Saif, Manuel Perez, Joaquim Soriano, Manuel Desco, Maria Victoria Gomez-Gaviro, Lorena Cusso, Diego Megias, Alexandra Aicher, Christopher Heeschen
The stromal microenvironment controls response to injury and inflammation, and is also an important determinant of cancer cell behavior. However, our understanding of its modulation by miRNA (miR) and their respective targets is still sparse. Here, we identified the miR-25-93-106b cluster and two new target genes as critical drivers for metastasis and immune evasion of cancer cells. Using miR-25-93-106b knockout mice or antagomiRs, we demonstrated regulation of the production of the chemoattractant CXCL12 controlling bone marrow metastasis...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28405520/the-immune-molecular-landscape-of-the-b7-and-tnfr-immunoregulatory-ligand-receptor-families-in-head-and-neck-cancer-a-comprehensive-overview-and-the-immunotherapeutic-implications
#12
Yu-Pei Chen, Jian Zhang, Ya-Qin Wang, Na Liu, Qing-Mei He, Xiao-Jing Yang, Ying Sun, Jun Ma
The B7 family and tumor necrosis factor receptor (TNFR) superfamily play a vital role in the T-cell co-stimulatory and co-inhibitory pathways, regulating T-cell activation, tolerance, and exhaustion; therapeutic modulation of these pathways is translated into effective new cancer treatments. Better understanding of the immune molecular landscapes of the B7 and TNFR families would guide head and neck immuno-oncology clinical research. We performed comprehensive molecular profiling of 10 B7 and 6 TNFR family members in head and neck cancer...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28178682/comprehensive-analysis-of-pd-l1-expression-in-glioblastoma-multiforme
#13
Dieter Henrik Heiland, Gerrit Haaker, Daniel Delev, Bianca Mercas, Waseem Masalha, Sabrina Heynckes, Annette Gäbelein, Dietmar Pfeifer, Maria Stella Carro, Astrid Weyerbrock, Marco Prinz, Oliver Schnell
Glioblastoma multiforme are highly malignant brain tumours with frequent genetic and epigenetic alterations. The poor clinical outcome of these tumours necessitates the development of new treatment options. Immunotherapies for glioblastoma multiforme including PD1/PD-L1 inhibition are currently tested in ongoing clinical trials. The purpose of this study was to investigate the molecular background of PD-L1 expression in glioblastoma multiforme and to find associated pathway activation and genetic alterations...
June 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28074529/epigenetic-mediated-immune-suppression-of-positive-co-stimulatory-molecules-in-chemoresistant-ovarian-cancer-cells
#14
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
https://www.readbyqxmd.com/read/28062906/programmed-cell-death-1-pathway-inhibition-in-myeloid-malignancies-implications-for-myeloproliferative-neoplasms
#15
REVIEW
D C Choi, D Tremblay, C Iancu-Rubin, J Mascarenhas
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic diseases that belong to the spectrum of myeloid malignancies (MyMs), which also include myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelogenous leukemia (CML). While hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic approach to many MyMs, the associated morbidity and mortality have necessitated the development of non-HSCT therapeutics for symptom management and disease course modification...
June 2017: Annals of Hematology
https://www.readbyqxmd.com/read/26681673/regulation-of-pd-l1-a-novel-role-of-pro-survival-signalling-in-cancer
#16
REVIEW
J Chen, C C Jiang, L Jin, X D Zhang
Evasion of immune system is a hallmark of cancer, which enables cancer cells to escape the attack from immune cells. Cancer cells can express many immune inhibitory signalling proteins to cause immune cell dysfunction and apoptosis. One of these inhibitory molecules is programmed death-ligand-1 (PD-L1), which binds to programmed death-1 (PD-1) expressed on T-cells, B-cells, dendritic cells and natural killer T-cells to suppress anti-cancer immunity. Therefore, anti-PD-L1 and anti-PD-1 antibodies have been used for the treatment of cancer, showing promising outcomes...
March 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/25633561/update-on-epstein-barr-virus-and-gastric-cancer-review
#17
REVIEW
Aya Shinozaki-Ushiku, Akiko Kunita, Masashi Fukayama
Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is a distinct subtype that accounts for nearly 10% of gastric carcinomas. EBVaGC is defined by monoclonal proliferation of carcinoma cells with latent EBV infection, as demonstrated by EBV-encoded small RNA (EBER) in situ hybridization. EBVaGC has characteristic clinicopathological features, including predominance among males, a proximal location in the stomach, lymphoepithelioma-like histology and a favorable prognosis. EBVaGC belongs to latency type I or II, in which EBERs, EBNA-1, BARTs, LMP-2A and BART miRNAs are expressed...
April 2015: International Journal of Oncology
https://www.readbyqxmd.com/read/25428504/predictive-correlates-of-response-to-the-anti-pd-l1-antibody-mpdl3280a-in-cancer-patients
#18
Roy S Herbst, Jean-Charles Soria, Marcin Kowanetz, Gregg D Fine, Omid Hamid, Michael S Gordon, Jeffery A Sosman, David F McDermott, John D Powderly, Scott N Gettinger, Holbrook E K Kohrt, Leora Horn, Donald P Lawrence, Sandra Rost, Maya Leabman, Yuanyuan Xiao, Ahmad Mokatrin, Hartmut Koeppen, Priti S Hegde, Ira Mellman, Daniel S Chen, F Stephen Hodi
The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding programmed death-1 (PD-1) and B7...
November 27, 2014: Nature
https://www.readbyqxmd.com/read/24162015/alterations-of-immune-response-of-non-small-cell-lung-cancer-with-azacytidine
#19
John Wrangle, Wei Wang, Alexander Koch, Hariharan Easwaran, Helai P Mohammad, Frank Vendetti, Wim Vancriekinge, Timothy Demeyer, Zhengzong Du, Princy Parsana, Kristen Rodgers, Ray-Whay Yen, Cynthia A Zahnow, Janis M Taube, Julie R Brahmer, Scott S Tykodi, Keith Easton, Richard D Carvajal, Peter A Jones, Peter W Laird, Daniel J Weisenberger, Salina Tsai, Rosalyn A Juergens, Suzanne L Topalian, Charles M Rudin, Malcolm V Brock, Drew Pardoll, Stephen B Baylin
Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples...
November 2013: Oncotarget
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