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https://www.readbyqxmd.com/read/28815041/-upregulation-of-cd47-by-the-endoplasmic-reticulum-stress-pathway-controls-anti-tumor-immune-responses
#1
Katherine L Cook, David R Soto-Pantoja
We recently demonstrated that targeting the unfolded protein response (UPR) protein GRP78 down-regulates CD47 expression, resulting in increased tumor macrophage infiltration and inhibited resistance to anti-estrogen therapy. We now show new data indicating that anti-estrogen therapy regulates CD47 expression and implicates its ligand, thrombospondin-1, in regulation of tumor macrophage infiltration. Moreover, GRP78 and CD47 co-expression is associated with poor prognosis in breast cancer patients, suggesting the existence of crosstalk between UPR and immunity that regulates therapeutic responses in breast cancer...
2017: Biomarker Research
https://www.readbyqxmd.com/read/28801364/cd47-is-not-over-expressed-in-fibrolamellar-hepatocellular-carcinoma
#2
Tabitha Cooney, Michael C Wei, Arun Rangaswami, Lei Xu, Julien Sage, Florette K Hazard
OBJECTIVES: CD47 is a transmembrane receptor that inhibits phagocytosis. Over-expression of CD47 is associated with an increased risk of tumor growth and metastasis. Clinical trials based on anti-CD47 therapy in adults are underway in a variety of malignancies. CD47 has been shown to be over-expressed in conventional hepatocellular carcinoma (HCC), a common liver tumor in adults. To our knowledge, there have been no studies to evaluate CD47 expression in the fibrolamellar subtype of HCC (FL-HCC), common in children and young adults...
August 2017: Annals of Clinical and Laboratory Science
https://www.readbyqxmd.com/read/28801234/dendritic-cells-but-not-macrophages-sense-tumor-mitochondrial-dna-for-cross-priming-through-signal-regulatory-protein-%C3%AE-signaling
#3
Meng Michelle Xu, Yang Pu, Dali Han, Yaoyao Shi, Xuezhi Cao, Hua Liang, Xiang Chen, Xiao-Dong Li, Liufu Deng, Zhijian J Chen, Ralph R Weichselbaum, Yang-Xin Fu
Inhibition of cytosolic DNA sensing represents a strategy that tumor cells use for immune evasion, but the underlying mechanisms are unclear. Here we have shown that CD47-signal regulatory protein α (SIRPα) axis dictates the fate of ingested DNA in DCs for immune evasion. Although macrophages were more potent in uptaking tumor DNA, increase of DNA sensing by blocking the interaction of SIRPα with CD47 preferentially occurred in dendritic cells (DCs) but not in macrophages. Mechanistically, CD47 blockade enabled the activation of NADPH oxidase NOX2 in DCs, which in turn inhibited phagosomal acidification and reduced the degradation of tumor mitochondrial DNA (mtDNA) in DCs...
August 15, 2017: Immunity
https://www.readbyqxmd.com/read/28783664/donor-sirp%C3%AE-polymorphism-modulates-the-innate-immune-response-to-allogeneic-grafts
#4
Hehua Dai, Andrew J Friday, Khodor I Abou-Daya, Amanda L Williams, Steven Mortin-Toth, Matthew L Nicotra, David M Rothstein, Warren D Shlomchik, Takashi Matozaki, Jeffrey S Isenberg, Martin H Oberbarnscheidt, Jayne S Danska, Fadi G Lakkis
Mice devoid of T, B, and natural killer (NK) cells distinguish between self and allogeneic nonself despite the absence of an adaptive immune system. When challenged with an allograft, they mount an innate response characterized by accumulation of mature, monocyte-derived dendritic cells (DCs) that produce interleukin-12 and present antigen to T cells. However, the molecular mechanisms by which the innate immune system detects allogeneic nonself to generate these DCs are not known. To address this question, we studied the innate response of Rag2(-/-) γc(-/-) mice, which lack T, B, and NK cells, to grafts from allogeneic donors...
June 23, 2017: Science Immunology
https://www.readbyqxmd.com/read/28770278/an-unbiased-in-vivo-functional-genomics-screening-approach-in-mice-identifies-novel-tumor-cell-based-regulators-of-immune-rejection
#5
Casey W Shuptrine, Reham Ajina, Elana J Fertig, Sandra A Jablonski, H Kim Lyerly, Zachary C Hartman, Louis M Weiner
The clinical successes of immune checkpoint therapies for cancer make it important to identify mechanisms of resistance to anti-tumor immune responses. Numerous resistance mechanisms have been identified employing studies of single genes or pathways, thereby parsing the tumor microenvironment complexity into tractable pieces. However, this limits the potential for novel gene discovery to in vivo immune attack. To address this challenge, we developed an unbiased in vivo genome-wide RNAi screening platform that leverages host immune selection in strains of immune-competent and immunodeficient mice to select for tumor cell-based genes that regulate in vivo sensitivity to immune attack...
August 2, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28769562/mithramycin-loaded-mpeg-plga-nanoparticles-exert-potent-antitumor-efficacy-against-pancreatic-carcinoma
#6
Xu-Jie Liu, Liang Li, Xiu-Jun Liu, Yi Li, Chun-Yan Zhao, Rui-Qi Wang, Yong-Su Zhen
Previous studies have shown that mithramycin A (MIT) is a promising candidate for the treatment of pancreatic carcinoma through inhibiting transcription factor Sp1. However, systemic toxicities may limit its clinical application. Here, we report a rationally designed formulation of MIT-loaded nanoparticles (MIT-NPs) with a small size and sustained release for improved passive targeting and enhanced therapeutic efficacy. Nearly spherical MIT-NPs with a mean particle size of 25.0±4.6 nm were prepared by encapsulating MIT into methoxy poly(ethylene glycol)-block-poly(d,l-lactic-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPs) with drug loading of 2...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28762749/thrombospondin-1-free-radicals-and-the-coronary-microcirculation-the-aging-conundrum
#7
Amanda Jo LeBlanc, Natia Q Kelm
SIGNIFICANCE: Successful matching of cardiac metabolism to perfusion is accomplished primarily through vasodilation of the coronary resistance arterioles, but the mechanism that achieves this effect changes significantly as aging progresses and involves the contribution of reactive oxygen species (ROS). Recent Advances: A matricellular protein, thrombospondin-1 (Thbs-1) has been shown to be a prolific contributor to the production and modulation of ROS in large conductance vessels and in the peripheral circulation...
August 1, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28745331/cd47-blockade-enhances-therapeutic-activity-of-tcr-mimic-antibodies-to-ultra-low-density-cancer-epitopes
#8
M D Mathias, J T Sockolosky, A Y Chang, K S Tan, C Liu, K C Garcia, D A Scheinberg
Leukemia accepted article preview online, 12 July 2017. doi:10.1038/leu.2017.223.
July 12, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28738534/high-expression-of-cd47-predicts-adverse-prognosis-in-chinese-patients-and-suppresses-immune-response-in-melanoma
#9
Wenhua Fu, Jisen Li, Wei Zhang, Peng Li
BACKGROUND: Cluster of differentiation 47 (CD47) negatively regulates macrophage phagocytosis and is correlated with adverse survival of multiple cancers. In melanoma patients, especially in Chinese melanoma patients, its prognostic value is unclear. In this study, we aim to study the prognostic value of CD47 in a Chinse melanoma patient cohort and its immunomodulation roles in mouse model. METHOD: 164 melanoma tissue specimens were collected. The expression of CD47 in these clinical samples was examined by immunohistochemistry staining (IHC)...
September 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28723893/in-vivo-crispr-screening-identifies-ptpn2-as-a-cancer-immunotherapy-target
#10
Robert T Manguso, Hans W Pope, Margaret D Zimmer, Flavian D Brown, Kathleen B Yates, Brian C Miller, Natalie B Collins, Kevin Bi, Martin W LaFleur, Vikram R Juneja, Sarah A Weiss, Jennifer Lo, David E Fisher, Diana Miao, Eliezer Van Allen, David E Root, Arlene H Sharpe, John G Doench, W Nicholas Haining
Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-γ signalling caused resistance to immunotherapy...
July 27, 2017: Nature
https://www.readbyqxmd.com/read/28714241/cytokine-profiles-in-tibetan-macaques-following-%C3%AE-1-3-galactosyltransferase-knockout-pig-liver-xenotransplantation
#11
Zhuochao Zhang, Xiao Li, Hong Zhang, Xuan Zhang, Hui Chen, Dengke Pan, Hongchen Ji, Liang Zhou, Juan Ling, Jingshi Zhou, Shuqiang Yue, Desheng Wang, Zhaoxu Yang, Kaishan Tao, Kefeng Dou
BACKGROUND: Pig-to-nonhuman primate orthotopic liver xenotransplantation is often accompanied by thrombocytopenia and coagulation disorders. Furthermore, the release of cytokines can trigger cascade reactions of coagulation and immune attacks within transplant recipients. To better elucidate the process of inflammation in liver xenograft recipients, we utilized a modified heterotopic auxiliary liver xenotransplantation model for xeno-immunological research. We studied the cytokine profiles and the relationship between cytokine levels and xenograft function after liver xenotransplantation...
July 17, 2017: Xenotransplantation
https://www.readbyqxmd.com/read/28712304/regulation-of-cellular-redox-signaling-by-matricellular-proteins-in-vascular-biology-immunology-and-cancer
#12
David D Roberts, Sukhbir Kaur, Jeffrey S Isenberg
SIGNIFICANCE: In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H2S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer...
July 16, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28703336/a-genome-wide-association-study-reveals-candidate-genes-for-the-supernumerary-nipple-phenotype-in-sheep-ovis-aries
#13
W-F Peng, S-S Xu, X Ren, F-H Lv, X-L Xie, Y-X Zhao, M Zhang, Z-Q Shen, Y-L Ren, L Gao, M Shen, J Kantanen, M-H Li
Genome-wide association studies (GWASs) have been widely applied in livestock to identify genes associated with traits of economic interest. Here, we conducted the first GWAS of the supernumerary nipple phenotype in Wadi sheep, a native Chinese sheep breed, based on Ovine Infinium HD SNP BeadChip genotypes in a total of 144 ewes (75 cases with four teats, including two normal and two supernumerary teats, and 69 control cases with two teats). We detected 63 significant SNPs at the chromosome-wise threshold. Additionally, one candidate region (chr1: 170...
July 12, 2017: Animal Genetics
https://www.readbyqxmd.com/read/28693236/significance-of-cd47-expression-in-gastric-cancer
#14
Tomoya Sudo, Yusuke Takahashi, Genta Sawada, Ryutaro Uchi, Koshi Mimori, Yoshito Akagi
Integrin-associated protein (CD47) is ubiquitously expressed on the surface of cells and functions as an identifier of self. In blood cancer, tumor cells expressing CD47 evade phagocytosis by macrophages, leading to a poor patient prognosis. However, the status of CD47 expression in solid tumors, particularly in gastric cancer, is not well understood. The purpose of the present study was to examine the level of CD47 in the primary tumor, peripheral blood (PB) and bone marrow (BM) of patients with gastric cancer, and to determine its effect...
July 2017: Oncology Letters
https://www.readbyqxmd.com/read/28670378/overexpression-of-cd47-predicts-poor-prognosis-and-promotes-cancer-cell-invasion-in-high-grade-serous-ovarian-carcinoma
#15
Yinuo Li, Shuhua Lu, Ying Xu, Chunping Qiu, Chengjuan Jin, Yuqiong Wang, Zhaojian Liu, Beihua Kong
CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. CD47 is overexpressed in various human malignancies. However, the expression and functional significance of CD47 in high-grade serous ovarian carcinoma (HGSOC) has not been completely understood. In this study, we reported that CD47 was commonly overexpressed in HGSOC. Higher CD47 expression was significantly correlated with poor prognosis of HGSOC patients. Functional investigations revealed that CD47 overexpression in ovarian cancer cells significantly promoted migration and invasion...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28669759/sirpa-inhibited-marrow-derived-macrophages-engorge-accumulate-and-differentiate-in-antibody-targeted-regression-of-solid-tumors
#16
Cory M Alvey, Kyle R Spinler, Jerome Irianto, Charlotte R Pfeifer, Brandon Hayes, Yuntao Xia, Sangkyun Cho, P C P Dave Dingal, Jake Hsu, Lucas Smith, Manu Tewari, Dennis E Discher
Marrow-derived macrophages are highly phagocytic, but whether they can also traffic into solid tumors and engulf cancer cells is questionable, given the well-known limitations of tumor-associated macrophages (TAMs). Here, SIRPα on macrophages from mouse and human marrow was inhibited to block recognition of its ligand, the "marker of self" CD47 on all other cells. These macrophages were then systemically injected into mice with fluorescent human tumors that had been antibody targeted. Within days, the tumors regressed, and single-cell fluorescence analyses showed that the more the macrophages engulfed, the more they accumulated within regressing tumors...
July 24, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28662400/linker-free-covalent-immobilization-of-heparin-sdf-1%C3%AE-and-cd47-on-ptfe-surface-for-antithrombogenicity-endothelialization-and-anti-inflammation
#17
Ang Gao, Ruiqiang Hang, Wan Li, Wei Zhang, Penghui Li, Guomin Wang, Long Bai, Xue-Feng Yu, Huaiyu Wang, Liping Tong, Paul K Chu
Small-diameter vascular grafts made of biomedical polytetrafluoroethylene (PTFE) suffer from the poor long-term patency rate originating from thrombosis and intimal hyperplasia, which can be ascribed to the insufficient endothelialization and chronic inflammation of the materials. Hence, bio-functionalization of PTFE grafts is highly desirable to circumvent these disadvantages. In this study, a versatile "implantation-incubation" approach in which the biomedical PTFE is initially modified by plasma immersion ion implantation (PIII) is described...
June 20, 2017: Biomaterials
https://www.readbyqxmd.com/read/28647567/stearoyl-coa-desaturase-regulates-sorafenib-resistance-via-modulation-of-er-stress-induced-differentiation
#18
Mark Kin Fai Ma, Eunice Yuen Ting Lau, Doris Hoi Wing Leung, Jessica Lo, Nicole Pui Yu Ho, Lily Kwan Wai Cheng, Stephanie Ma, Chi Ho Lin, John A Copland, Jin Ding, Regina Cheuk Lam Lo, Irene Oi Lin Ng, Terence Kin Wah Lee
BACKGROUND & AIMS: We investigated the functional role and clinical significance of stearoyl-CoA desaturase-1 (SCD1) mediated endoplasmic reticulum (ER) stress in regulating liver tumor-initiating cells (T-ICs) and sorafenib resistance, with the aim of developing a novel therapeutic strategy against hepatocellular carcinomas (HCCs). METHODS: We evaluated the clinic-pathological relevance of SCD1 and its correlation with sorafenib resistance in large cohorts of HCC clinical samples by qPCR and immunohistochemical analyses...
June 22, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28644129/anti-cd47-antibodies-induce-phagocytosis-of-live-malignant-b-cells-by-macrophages-via-the-fc-domain-resulting-in-cell-death-by-phagoptosis
#19
Lucy E Métayer, Anna Vilalta, G A Amos Burke, Guy C Brown
When expressed on the surface of cells, CD47 inhibits phagocytosis of these cells by phagocytes. Most human cancers overexpress CD47, and antibodies to CD47 have shown a remarkable ability to clear a range of cancers in animal models. However, the mechanism by which these antibodies cause cancer cell death is unclear. We find that CD47 is expressed on the surface of three B-cell lines from human malignancies: 697 (pre-B-ALL lymphoblasts), Ramos and DG-75 (both mature B-cells, Burkitt's lymphoma), and anti-CD47 antibodies greatly increase the phagocytosis of all three cell line by macrophages...
June 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28638734/severe-but-not-mild-heat-shock-treatment-induces-immunogenic-cell-death-in-cancer-cells
#20
Irena Adkins, Lenka Sadilkova, Nada Hradilova, Jakub Tomala, Marek Kovar, Radek Spisek
The mechanisms of immunogenicity underlying mild heat-shock (mHS) treatment < 42°C of tumor cells are largely attributed to the action of heat-shock proteins; however, little is known about the immunogenicity of tumor cells undergoing severe cytotoxic heat-shock treatment (sHS > 43°C). Here, we found that sHS, but not mHS (42°C), induces immunogenic cell death in human cancer cell lines as defined by the induction of ER stress response and ROS generation, cell surface exposure of calreticulin, HSP70 and HSP90, decrease of cell surface CD47, release of ATP and HMGB1...
2017: Oncoimmunology
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