542 results on '"Taylor-Papadimitriou, J"'
Search Results
152. Complexity of expression of antigenic determinants, recognized by monoclonal antibodies HMFG-1 and HMFG-2, in normal and malignant human mammary epithelial cells.
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Burchell, J, primary, Durbin, H, additional, and Taylor-Papadimitriou, J, additional
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- 1983
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153. Monoclonal antikeratin antibodies in the study of differentiation and malignancy in the human breast
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Bartek, J., primary, Durban, E., additional, Taylor-Papadimitriou, J., additional, Hallowes, R.C., additional, and Millis, R., additional
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- 1985
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154. The Differential Diagnosis of Routinely Processed Anaplastic Tumors Using Monoclonal Antibodies
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Gatter, K.C., primary, Alcock, C., additional, Heryet, A., additional, Pulford, K.A., additional, Heyderman, E., additional, Taylor-Papadimitriou, J., additional, Stein, H., additional, and Mason, D.Y., additional
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- 1985
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155. The hypervariable gene locus PUM, which codes for the tumour associated epithelial mucins, is located on chromosome 1, within the region 1g21?24
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SWALLOW, D. M., primary, GENDLER, S., additional, GRIFFITHS, B., additional, KEARNEY, A., additional, POVEY, S., additional, SHEER, D., additional, PALMER, R. W., additional, and TAYLOR-PAPADIMITRIOU, J., additional
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- 1987
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156. Vergleich der Darstellung von Resttumorgewebe bei Ovarialkarzinompatientinnen mittels Immunszintigraphie mit Jod-131-markierten monoklonalen Antikörpern HMFG2und HMFG1F(ab′)2gegenüber der Computertomographie
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Pectasides, D., primary, Pateniotis, K., additional, Tzimis, L., additional, Trapalli, X., additional, Natsis, P., additional, Arapantoni, P., additional, Taylor-Papadimitriou, J., additional, Epenetos, A., additional, Koutsiouba, P., additional, and Athanassiou, A., additional
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- 1989
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157. Identification of immunoreactive monoclonal antibody fragments for improved immunoscintigraphy
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Mather, S.J., primary, Durbin, H., additional, and Taylor-Papadimitriou, J., additional
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- 1987
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158. Incorporation of Labeled Precursors into Nuclear and Mitochondrial DNA of Cells Grown in Culture
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Georgatsos, J. G., primary, Taylor-Papadimitriou, J., additional, and Karemfyllis, T., additional
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- 1972
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159. New methods in peptide synthesis. Part V. On α- and γ-diphenylmethyl and phenacyl esters ofL-glutamic acid
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Taylor-Papadimitriou, J., primary, Yovanidis, C., additional, Paganou, A., additional, and Zervas, L., additional
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- 1967
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160. ChemInform Abstract: CYSTEIN UND CYSTEINPEPTIDE 5. MITT. S-TRITYL- UND S-DIPHENYLMETHYL-CYSTEIN UND -CYSTEINPEPTIDE 6. MITT. S-ACYLCYSTEINE IN DER PEPTIDSYNTH.
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PHOTAKI, I., primary, TAYLOR-PAPADIMITRIOU, J., additional, SAKARELLOS, C., additional, MAZARAKIS, P., additional, and ZERVAS, L., additional
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- 1971
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161. Interferon affects both G1and S+G2in cells stimulated from quiescence to growth
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BALKWILL, F. and TAYLOR-PAPADIMITRIOU, J.
- Abstract
THE interferons were originally described as proteins, produced by cells in response to virus infection, which could induce viral resistance in cells of the same species1. It is becoming clear that these proteins have other important biological activities2and can inhibit cell division in both normal and malignant cells3–5. Although the phenomenon of growth inhibition by interferon is well established, data analysis of the effect in terms of the cell cycle is limited and not completely consistent. Killander et al.6 and Matarese and Rossi7, using asynchronously growing cultures of L1210 and Friend leukaemia cells respectively, have found that interferon-treated cells are delayed in both G1and G2, and we have recently observed a similar effect of interferon on asynchronously growing MCF-7 cells8. Sokawa et al. have reported, however, that the only parameter affected in interferon-treated quiescent BALB/c 3T3 cells after serum stimulation, is their rate of entry into S (ref. 9). It is possible that the effect of interferon on the cell cycle of asynchronous transformed cells is different, in terms of cell cycle parameters, from its effect on quiescent untransformed cells. In an attempt to clarify this point, we have examined in detail the effect of interferon on the passage of serum-stimulated cells through the cell cycle, using BALB/c 3T3 and Swiss 3T3K cells, and a strain of human embryo lung diploid fibroblasts, HEL 27. In contrast to Sokawa et al., we have found that both G1and S+G2are extended by interferon treatment of all three cell types studied.
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- 1978
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162. Cancer vaccines and the polymorphic epithelial mucin
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Taylor-Papadimitriou, J., Peat, N., Graham, R., and Burchell, J.
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Vaccines -- Research ,Cancer -- Physiological aspects ,Business ,Health care industry - Abstract
According to an abstract submitted by the authors to the International Symposium on Cancer Vaccines, held October 3-5, 1994, in New York, New York, 'The recruitment of the different compartments [...]
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- 1995
163. Epithelial cancer mucin antigens: the products of abnormal glycosylation
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Taylor-Papadimitriou, J.
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Glycosylation -- Physiological aspects ,Epithelial tumors -- Physiological aspects ,Mucins -- Physiological aspects ,Health ,Science and technology - Abstract
AUTHORS: J. Taylor-Papadimitriou. 44 Lincoln's Inn Fields, London, U.K. According to an abstract presented by the author to the Specific Immunotherapy of Cancer Vaccines Conference, held January 21-24, 1993, in [...]
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- 1993
164. Vergleich der Darstellung von Resttumorgewebe bei Ovarialkarzinompatientinnen mittels Immunszintigraphie mit Jod-131-markierten monoklonalen Antikörpern HMFG2 und HMFG1 F(ab′)2 gegenüber der Computertomographie
- Author
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Pectasides, D., Pateniotis, K., Tzimis, L., Trapalli, X., Natsis, P., Arapantoni, P., Taylor-Papadimitriou, J., Epenetos, A., Koutsiouba, P., and Athanassiou, A.
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- 1989
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165. Professor Mike Price
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Taylor-Papadimitriou, J.
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- 2001
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166. The Humoral Immune Response to Monoclonal Antibody Therapy for Ovarian Cancer
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Nicholson, S, Gallop, JL, Band, H, Taylor-Papadimitriou, J, George, AJT, and Thomas, H
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- 1998
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167. Human lymphoblastoid interferon can inhibit the growth of human breast cancer xenografts in athymic (nude) mice
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Balkwill, F., Taylor-Papadimitriou, J., Fantes, K.H., and Sebesteny, A.
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- 1980
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168. Biology, biochemistry and immunology of carcinoma-associated mucins
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Taylor-Papadimitriou, J
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- 1997
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169. Exploiting altered glycosylation patterns in cancer: progress and challenges in diagnosis and therapy
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Taylor-Papadimitriou, J. and Epenetos, A. A.
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- 1994
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170. News of the growth business
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Taylor-Papadimitriou, J.
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- 1983
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171. Antibody-guided irradiation of malignant ascites in ovarian cancer: a new therapeutic method possessing specificity against cancer cells
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Taylor-Papadimitriou, J
- Published
- 1986
172. 175 - The KDM5B demethylase in the normal and malignant mammary gland.
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Kogera, F., Steven, C., Spencer-Dene, B., Picco, G., Tajadura-Ortega, V., Chen, Y.H., Bennett, E., Quist, J., Taylor-Papadimitriou, J., and Burchell, J.
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- 2016
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173. Histone Methylases and Demethylases Regulating Antagonistic Methyl Marks: Changes Occurring in Cancer.
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Taylor-Papadimitriou J and Burchell JM
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- Animals, Epigenesis, Genetic, Humans, Lysine metabolism, Polycomb-Group Proteins metabolism, Histone Demethylases metabolism, Histone Methyltransferases metabolism, Histones metabolism, Neoplasms genetics
- Abstract
Epigenetic regulation of gene expression is crucial to the determination of cell fate in development and differentiation, and the Polycomb (PcG) and Trithorax (TrxG) groups of proteins, acting antagonistically as complexes, play a major role in this regulation. Although originally identified in Drosophila, these complexes are conserved in evolution and the components are well defined in mammals. Each complex contains a protein with methylase activity (KMT), which can add methyl groups to a specific lysine in histone tails, histone 3 lysine 27 (H3K27), by PcG complexes, and H3K4 and H3K36 by TrxG complexes, creating transcriptionally repressive or active marks, respectively. Histone demethylases (KDMs), identified later, added a new dimension to histone methylation, and mutations or changes in levels of expression are seen in both methylases and demethylases and in components of the PcG and TrX complexes across a range of cancers. In this review, we focus on both methylases and demethylases governing the methylation state of the suppressive and active marks and consider their action and interaction in normal tissues and in cancer. A picture is emerging which indicates that the changes which occur in cancer during methylation of histone lysines can lead to repression of genes, including tumour suppressor genes, or to the activation of oncogenes. Methylases or demethylases, which are themselves tumour suppressors, are highly mutated. Novel targets for cancer therapy have been identified and a methylase (KMT6A/EZH2), which produces the repressive H3K27me3 mark, and a demethylase (KDM1A/LSD1), which demethylates the active H3K4me2 mark, are now under clinical evaluation.
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- 2022
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174. KDM5B protein expressed in viable and fertile ΔARID mice exhibit no demethylase activity.
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Jamshidi S, Catchpole S, Chen J, So CWE, Burchell J, Rahman KM, and Taylor-Papadimitriou J
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- Animals, DNA Demethylation, DNA-Binding Proteins genetics, DNA-Binding Proteins ultrastructure, Enzyme Assays, Female, Fertility genetics, Gene Expression Regulation, Developmental, Jumonji Domain-Containing Histone Demethylases genetics, Jumonji Domain-Containing Histone Demethylases ultrastructure, Male, Mice, Mice, Transgenic, Molecular Dynamics Simulation, Protein Processing, Post-Translational genetics, DNA-Binding Proteins metabolism, Epigenesis, Genetic, Jumonji Domain-Containing Histone Demethylases metabolism, Protein Domains genetics
- Abstract
Post‑translational modification of histones serve a crucial role in the control of gene transcription. Trimethylation of lysine 4 on histone 3 is associated with transcription activation. There are currently six known methylases and six known demethylases that can control the methylation status of this site. Lysine demethylase 5B (KDM5B) is one such demethylase, which can repress gene expression. In particular KDM5B has been found to be overexpressed in a number of cancer types, and small‑molecular weight inhibitors of its demethylase activity have been identified. Previous characterisation of Kdm5b knock‑out mice has revealed that this genotype leads to either embryonic or neonatal lethality. However, the ΔA‑T rich interaction domain (ΔARID)‑KDM5B strain of mice, which have the ARID domain and five amino acids within the Jumonji (Jmj)N domain spliced out from KDM5B, remain viable and fertile. In the present study, ΔARID‑KDM5B was found to have no demethylase activity as determined by in vitro demethylase assays and by immunofluorescence in transfected Cos‑1 cells. Furthermore, molecular dynamic simulations revealed conformational changes within the ΔARID‑KDM5B structure compared with that in WT‑KDM5B, particularly in the JmjC domain, which is responsible for the catalytic activity of WT‑KDM5B. This supports the experimental data that shows the loss of demethylase activity. Since Kdm5b knock‑out mice show varying degrees of lethality, these data suggest that KDM5B serves a crucial function in development in a manner that is independent of its demethylase activity.
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- 2021
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175. O-linked mucin-type glycosylation regulates the transcriptional programme downstream of EGFR.
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Tajadura-Ortega V, Gambardella G, Skinner A, Halim A, Van Coillie J, Schjoldager KTG, Beatson R, Graham R, Achkova D, Taylor-Papadimitriou J, Ciccarelli FD, and Burchell JM
- Subjects
- Breast Neoplasms pathology, ErbB Receptors metabolism, Female, Glycosylation, Humans, Receptors, Estrogen metabolism, Breast Neoplasms metabolism, Mucin-1 metabolism
- Abstract
Aberrant mucin-type O-linked glycosylation is a common occurrence in cancer where the upregulation of sialyltransferases is often seen leading to the early termination of O-glycan chains. Mucin-type O-linked glycosylation is not limited to mucins and occurs on many cell surface glycoproteins including EGFR, where the number of sites can be limited. Upon EGF ligation, EGFR induces a signaling cascade and may also translocate to the nucleus where it directly regulates gene transcription, a process modulated by Galectin-3 and MUC1 in some cancers. Here, we show that upon EGF binding, breast cancer cells carrying different O-glycans respond by transcribing different gene expression signatures. MMP10, the principal gene upregulated when cells carrying sialylated core 1 glycans were stimulated with EGF, is also upregulated in ER-positive breast carcinoma reported to express high levels of ST3Gal1 and hence mainly core 1 sialylated O-glycans. In contrast, isogenic cells engineered to carry core 2 glycans upregulate CX3CL1 and FGFBP1 and these genes are upregulated in ER-negative breast carcinomas, also known to express longer core 2 O-glycans. Changes in O-glycosylation did not significantly alter signal transduction downstream of EGFR in core 1 or core 2 O-glycan expressing cells. However, striking changes were observed in the formation of an EGFR/galectin-3/MUC1/β-catenin complex at the cell surface that is present in cells carrying short core 1-based O-glycans but absent in core 2 carrying cells., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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176. Cancer-associated hypersialylated MUC1 drives the differentiation of human monocytes into macrophages with a pathogenic phenotype.
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Beatson R, Graham R, Grundland Freile F, Cozzetto D, Kannambath S, Pfeifer E, Woodman N, Owen J, Nuamah R, Mandel U, Pinder S, Gillett C, Noll T, Bouybayoune I, Taylor-Papadimitriou J, and Burchell JM
- Subjects
- Breast Neoplasms genetics, Breast Neoplasms metabolism, Cell Differentiation, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Mucin-1 genetics, Macrophages physiology, Monocytes physiology, Mucin-1 metabolism
- Abstract
The tumour microenvironment plays a crucial role in the growth and progression of cancer, and the presence of tumour-associated macrophages (TAMs) is associated with poor prognosis. Recent studies have demonstrated that TAMs display transcriptomic, phenotypic, functional and geographical diversity. Here we show that a sialylated tumour-associated glycoform of the mucin MUC1, MUC1-ST, through the engagement of Siglec-9 can specifically and independently induce the differentiation of monocytes into TAMs with a unique phenotype that to the best of our knowledge has not previously been described. These TAMs can recruit and prolong the lifespan of neutrophils, inhibit the function of T cells, degrade basement membrane allowing for invasion, are inefficient at phagocytosis, and can induce plasma clotting. This macrophage phenotype is enriched in the stroma at the edge of breast cancer nests and their presence is associated with poor prognosis in breast cancer patients.
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- 2020
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177. O-linked mucin-type glycosylation in breast cancer.
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Burchell JM, Beatson R, Graham R, Taylor-Papadimitriou J, and Tajadura-Ortega V
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- Acetylgalactosamine metabolism, Biological Transport, Breast Neoplasms immunology, Breast Neoplasms pathology, Disease Progression, Female, Gene Expression Regulation, Enzymologic, Glycoside Hydrolases genetics, Glycoside Hydrolases metabolism, Glycosylation, Glycosyltransferases genetics, Glycosyltransferases metabolism, Golgi Apparatus enzymology, Golgi Apparatus metabolism, Humans, Hydrogen-Ion Concentration, Neoplasm Metastasis, Tumor Microenvironment, Breast Neoplasms metabolism, Mucin-1 metabolism
- Abstract
Changes in mucin-type O-linked glycosylation are seen in over 90% of breast cancers where increased sialylation is often observed and a change from branched glycans to linear glycans is often seen. There are many mechanisms involved including increased/altered expression of glycosyltransferases and relocalisation to the endoplasmic reticulum of the enzymes responsible for the addition of the first sugar, N -acetyl-d-galactosamine. It is now becoming clear that these changes can contribute to tumour growth and progression by modulating the micro-environment through glycan-sensing lectins expressed on immune cells, by modulating interactions with tumour surface receptors and by binding to selectins. The understanding of how changes in mucin-type O-linked glycosylation influence tumour growth and progression reveals new potential targets for therapeutic intervention in the treatment of breast cancer., (© 2018 The Author(s).)
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- 2018
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178. Latest developments in MUC1 immunotherapy.
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Taylor-Papadimitriou J, Burchell JM, Graham R, and Beatson R
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- Antimetabolites, Antineoplastic therapeutic use, Clinical Trials as Topic, Combined Modality Therapy, Deoxycytidine analogs & derivatives, Deoxycytidine therapeutic use, Glycosylation, Humans, Mucin-1 chemistry, Mucin-1 physiology, Neoplasms drug therapy, Tumor Microenvironment, Gemcitabine, Immunotherapy, Mucin-1 immunology, Neoplasms therapy
- Abstract
Currently, there is renewed interest in attempting to recruit the host immune system to eliminate cancers, and within this renewed activity, MUC1 continues to arouse interest. MUC1 has been considered a possible therapeutic target for the past 30 years as it is up-regulated, aberrantly glycosylated and its polarization is lost in many adenocarcinomas. Moreover, MUC1 is expressed by some haematopoietic cancers, including acute myeloid leukaemia and myeloma. Although multiple clinical trials have been initiated and immune responses have been documented, effective clinical benefit worthy of approval for general application has not as yet been achieved. However, this does not appear to have quelled the interest in MUC1 as a therapeutic target, as shown by the increase in the number of MUC1-based clinical trials initiated in 2017 ( Figure 1). As with all translational studies, incorporating new relevant research findings into therapeutic strategy is difficult. Decisions are made to commit to a specific strategy based on the information and data available when the trial is initiated. However, the time required for preclinical studies and early trials can render the founding concept not always appropriate for proceeding to a larger definitive trial. Here, we summarize the attempts made, to date, to bring MUC1 into the world of cancer immunotherapy and discuss how research findings regarding MUC1 structure and function together with expanded knowledge of its interactions with the tumour environment and immune effector cells could lead to improved therapeutic approaches. ppbiost;46/3/659/BST20170400CF1F1BST-2017-0400CF1Figure 1.Number of MUC1-targeted trials initiated each year., (© 2018 The Author(s).)
- Published
- 2018
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179. JARID1/KDM5 demethylases as cancer targets?
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Taylor-Papadimitriou J and Burchell J
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- Histone Demethylases antagonists & inhibitors, Humans, Jumonji Domain-Containing Histone Demethylases antagonists & inhibitors, Neoplasms enzymology, Neoplasms genetics, Nuclear Proteins antagonists & inhibitors, Repressor Proteins antagonists & inhibitors, Retinoblastoma-Binding Protein 2 antagonists & inhibitors, Antineoplastic Agents pharmacology, Molecular Targeted Therapy, Neoplasms drug therapy
- Published
- 2017
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180. Targeting of Tumor-Associated Glycoforms of MUC1 with CAR T Cells.
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Maher J, Wilkie S, Davies DM, Arif S, Picco G, Julien S, Foster J, Burchell J, and Taylor-Papadimitriou J
- Subjects
- Antigens, Neoplasm, Glycosylation, Humans, Neoplasms immunology, Mucin-1 immunology, T-Lymphocytes immunology
- Abstract
We read with interest the manuscript by June and colleagues published recently in Immunity in which they describe targeting of aberrantly glycosylated tumor-associated cell membrane mucin MUC1 using chimeric antigen receptor-engineered human T cells (Posey et al., 2016). In that study, the authors used a second generation 4-1BB costimulatory-molecule-based chimeric antigen receptor (CAR) (Imai et al., 2004) in which targeting was achieved using a single-chain variable fragment (scFv) derived from the 5E5 antibody. This CAR selectively binds MUC1 that carries the Tn or sialyl (S)Tn glycan. Both of these truncated glycans are aberrantly expressed on the MUC1 glycoprotein in a spectrum of malignancies and consequently represent attractive targets for immunotherapeutic exploitation., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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181. The mucin MUC1 modulates the tumor immunological microenvironment through engagement of the lectin Siglec-9.
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Beatson R, Tajadura-Ortega V, Achkova D, Picco G, Tsourouktsoglou TD, Klausing S, Hillier M, Maher J, Noll T, Crocker PR, Taylor-Papadimitriou J, and Burchell JM
- Subjects
- Antigens, CD genetics, Biomarkers, Cell Differentiation, Cell Line, Dendritic Cells immunology, Dendritic Cells metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, Gene Expression, Glycosylation, Humans, Macrophages immunology, Macrophages metabolism, Mitogen-Activated Protein Kinases metabolism, Myeloid Cells cytology, Myeloid Cells immunology, Myeloid Cells metabolism, Neoplasms genetics, Neoplasms pathology, Phenotype, Protein Binding, Sialic Acid Binding Immunoglobulin-like Lectins genetics, Antigens, CD metabolism, Mucin-1 metabolism, Neoplasms immunology, Neoplasms metabolism, Sialic Acid Binding Immunoglobulin-like Lectins metabolism, Tumor Microenvironment immunology
- Abstract
Siglec-9 is a sialic-acid-binding lectin expressed predominantly on myeloid cells. Aberrant glycosylation occurs in essentially all types of cancers and results in increased sialylation. Thus, when the mucin MUC1 is expressed on cancer cells, it is decorated by multiple short, sialylated O-linked glycans (MUC1-ST). Here we found that this cancer-specific MUC1 glycoform, through engagement of Siglec-9, 'educated' myeloid cells to release factors associated with determination of the tumor microenvironment and disease progression. Moreover, MUC1-ST induced macrophages to display a tumor-associated macrophage (TAM)-like phenotype, with increased expression of the checkpoint ligand PD-L1. Binding of MUC1-ST to Siglec-9 did not activate the phosphatases SHP-1 or SHP-2 but, unexpectedly, induced calcium flux that led to activation of the kinases MEK-ERK. This work defines a critical role for aberrantly glycosylated MUC1 and identifies an activating pathway that follows engagement of Siglec-9., Competing Interests: J.M.B. is a consultant to the company Palleon Pharma and P.R.C. is a scientific co-founder of Palleon Pharma. All other authors declare no competing financial interests.
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- 2016
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182. Elevated IgG4 in patient circulation is associated with the risk of disease progression in melanoma.
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Karagiannis P, Villanova F, Josephs DH, Correa I, Van Hemelrijck M, Hobbs C, Saul L, Egbuniwe IU, Tosi I, Ilieva KM, Kent E, Calonje E, Harries M, Fentiman I, Taylor-Papadimitriou J, Burchell J, Spicer JF, Lacy KE, Nestle FO, and Karagiannis SN
- Abstract
Emerging evidence suggests pathological and immunoregulatory functions for IgG4 antibodies and IgG4
+ B cells in inflammatory diseases and malignancies. We previously reported that IgG4 antibodies restrict activation of immune effector cell functions and impair humoral responses in melanoma. Here, we investigate IgG4 as a predictor of risk for disease progression in a study of human sera (n = 271: 167 melanoma patients; 104 healthy volunteers) and peripheral blood B cells (n = 71: 47 melanoma patients; 24 healthy volunteers). IgG4 (IgG4/IgGtotal ) serum levels were elevated in melanoma. High relative IgG4 levels negatively correlated with progression-free survival (PFS) and overall survival. In early stage (I-II) disease, serum IgG4 was independently negatively prognostic for progression-free survival, as was elevation of IgG4+ circulating B cells (CD45+ CD22+ CD19+ CD3- CD14- ). In human tissues (n = 256; 108 cutaneous melanomas; 56 involved lymph nodes; 60 distant metastases; 32 normal skin samples) IgG4+ cell infiltrates were found in 42.6% of melanomas, 21.4% of involved lymph nodes and 30% of metastases, suggesting inflammatory conditions that favor IgG4 at the peripheral and local levels. Consistent with emerging evidence for an immunosuppressive role for IgG4, these findings indicate association of elevated IgG4 with disease progression and less favorable clinical outcomes. Characterizing immunoglobulin and other humoral immune profiles in melanoma might identify valuable prognostic tools for patient stratification and in the future lead to more effective treatments less prone to tumor-induced blockade mechanisms.- Published
- 2015
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183. The Breast Cancer-Associated Glycoforms of MUC1, MUC1-Tn and sialyl-Tn, Are Expressed in COSMC Wild-Type Cells and Bind the C-Type Lectin MGL.
- Author
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Beatson R, Maurstad G, Picco G, Arulappu A, Coleman J, Wandell HH, Clausen H, Mandel U, Taylor-Papadimitriou J, Sletmoen M, and Burchell JM
- Subjects
- Cell Line, Tumor, Female, Humans, Protein Binding, Antigens, Tumor-Associated, Carbohydrate metabolism, Breast Neoplasms metabolism, Lectins, C-Type metabolism, Mucin-1 metabolism
- Abstract
Aberrant glycosylation occurs in the majority of human cancers and changes in mucin-type O-glycosylation are key events that play a role in the induction of invasion and metastases. These changes generate novel cancer-specific glyco-antigens that can interact with cells of the immune system through carbohydrate binding lectins. Two glyco-epitopes that are found expressed by many carcinomas are Tn (GalNAc-Ser/Thr) and STn (NeuAcα2,6GalNAc-Ser/Thr). These glycans can be carried on many mucin-type glycoproteins including MUC1. We show that the majority of breast cancers carry Tn within the same cell and in close proximity to extended glycan T (Galβ1,3GalNAc) the addition of Gal to the GalNAc being catalysed by the T synthase. The presence of active T synthase suggests that loss of the private chaperone for T synthase, COSMC, does not explain the expression of Tn and STn in breast cancer cells. We show that MUC1 carrying both Tn or STn can bind to the C-type lectin MGL and using atomic force microscopy show that they bind to MGL with a similar dead adhesion force. Tumour associated STn is associated with poor prognosis and resistance to chemotherapy in breast carcinomas, inhibition of DC maturation, DC apoptosis and inhibition of NK activity. As engagement of MGL in the absence of TLR triggering may lead to anergy, the binding of MUC1-STn to MGL may be in part responsible for some of the characteristics of STn expressing tumours.
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- 2015
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184. Targeting DNGR-1 (CLEC9A) with antibody/MUC1 peptide conjugates as a vaccine for carcinomas.
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Picco G, Beatson R, Taylor-Papadimitriou J, and Burchell JM
- Subjects
- Animals, CD8-Positive T-Lymphocytes immunology, HLA-A2 Antigen immunology, Humans, Mice, Mice, Inbred C57BL, Antibodies immunology, Cancer Vaccines immunology, Lectins, C-Type immunology, Mucin-1 immunology, Receptors, Mitogen immunology
- Abstract
DCs are the most potent APCs and are the focus of many immunotherapeutic approaches for the treatment of cancer, although most of these approaches require the ex vivo generation and pulsing of DCs. We have targeted a subset of DCs in vivo using an Ab to DNGR-1, a C-type lectin dedicated to the cross-presentation of Ag expressed by subsets of DCs. HLA-A2 epitopes from the tumour-associated Ag, MUC1, were coupled to the anti-DNGR-1 Ab, and their efficacy in generating a Th1-cell response and inhibiting tumour growth was evaluated in a clinically relevant double transgenic mouse model expressing human MUC1 and A2K/b. Using this strategy, we demonstrate that an effective immune response to MUC1 can be generated, which results in a significant delay in the growth of MUC1-expressing tumours in both prophylactic and therapeutic settings. In addition, we also show, using PBMCs isolated from healthy volunteer blood, that target an MUC1 HLA-A2 epitope to human DNGR-1 in vitro can induce an MUC1-specific CD8(+) -T-cell response, which confirms the relevance of our in vivo murine results in the human setting., (© 2014 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA Weinheim.)
- Published
- 2014
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185. The human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter.
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Hasan UA, Zannetti C, Parroche P, Goutagny N, Malfroy M, Roblot G, Carreira C, Hussain I, Müller M, Taylor-Papadimitriou J, Picard D, Sylla BS, Trinchieri G, Medzhitov R, and Tommasino M
- Subjects
- Base Sequence, Cell Line, Tumor, Cervix Uteri immunology, Cervix Uteri metabolism, Cervix Uteri virology, Down-Regulation genetics, Epithelial Cells immunology, Epithelial Cells metabolism, Epithelial Cells virology, Female, HEK293 Cells, HeLa Cells, Host-Pathogen Interactions genetics, Host-Pathogen Interactions immunology, Humans, Molecular Sequence Data, Papillomavirus Infections genetics, Papillomavirus Infections immunology, Papillomavirus Infections virology, Promoter Regions, Genetic, Repressor Proteins metabolism, Human papillomavirus 16 immunology, Human papillomavirus 16 pathogenicity, Papillomavirus E7 Proteins immunology, Toll-Like Receptor 9 genetics
- Abstract
Human papillomavirus type 16 (HPV16) and other oncogenic viruses have been reported to deregulate immunity by suppressing the function of the double-stranded DNA innate sensor TLR9. However, the mechanisms leading to these events remain to be elucidated. We show that infection of human epithelial cells with HPV16 promotes the formation of an inhibitory transcriptional complex containing NF-κBp50-p65 and ERα induced by the E7 oncoprotein. The E7-mediated transcriptional complex also recruited the histone demethylase JARID1B and histone deacetylase HDAC1. The entire complex bound to a specific region on the TLR9 promoter, which resulted in decreased methylation and acetylation of histones upstream of the TLR9 transcriptional start site. The involvement of NF-κB and ERα in the TLR9 down-regulation by HPV16 E7 was fully confirmed in cervical tissues from human patients. Importantly, we present evidence that the HPV16-induced TLR9 down-regulation affects the interferon response which negatively regulates viral infection. Our studies highlight a novel HPV16-mediated mechanism that combines epigenetic and transcriptional events to suppress a key innate immune sensor.
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- 2013
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186. Autoantibodies to MUC1 glycopeptides cannot be used as a screening assay for early detection of breast, ovarian, lung or pancreatic cancer.
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Burford B, Gentry-Maharaj A, Graham R, Allen D, Pedersen JW, Nudelman AS, Blixt O, Fourkala EO, Bueti D, Dawnay A, Ford J, Desai R, David L, Trinder P, Acres B, Schwientek T, Gammerman A, Reis CA, Silva L, Osório H, Hallett R, Wandall HH, Mandel U, Hollingsworth MA, Jacobs I, Fentiman I, Clausen H, Taylor-Papadimitriou J, Menon U, and Burchell JM
- Subjects
- Adult, Aged, Breast Neoplasms blood, Breast Neoplasms immunology, Carcinoma blood, Carcinoma immunology, Case-Control Studies, Cohort Studies, Female, Glycopeptides immunology, Humans, Immunoassay, Lung Neoplasms blood, Lung Neoplasms immunology, Middle Aged, Ovarian Neoplasms blood, Ovarian Neoplasms immunology, Pancreatic Neoplasms blood, Pancreatic Neoplasms immunology, Autoantibodies blood, Breast Neoplasms diagnosis, Carcinoma diagnosis, Early Detection of Cancer methods, Lung Neoplasms diagnosis, Mucin-1 immunology, Ovarian Neoplasms diagnosis, Pancreatic Neoplasms diagnosis
- Abstract
Background: Autoantibodies have been detected in sera before diagnosis of cancer leading to interest in their potential as screening/early detection biomarkers. As we have found autoantibodies to MUC1 glycopeptides to be elevated in early-stage breast cancer patients, in this study we analysed these autoantibodies in large population cohorts of sera taken before cancer diagnosis., Methods: Serum samples from women who subsequently developed breast cancer, and aged-matched controls, were identified from UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and Guernsey serum banks to formed discovery and validation sets. These were screened on a microarray platform of 60mer MUC1 glycopeptides and recombinant MUC1 containing 16 tandem repeats. Additional case-control sets comprised of women who subsequently developed ovarian, pancreatic and lung cancer were also screened on the arrays., Results: In the discovery (273 cases, 273 controls) and the two validation sets (UKCTOCS 426 cases, 426 controls; Guernsey 303 cases and 606 controls), no differences were found in autoantibody reactivity to MUC1 tandem repeat peptide or glycoforms between cases and controls. Furthermore, no differences were observed between ovarian, pancreatic and lung cancer cases and controls., Conclusion: This robust, validated study shows autoantibodies to MUC1 peptide or glycopeptides cannot be used for breast, ovarian, lung or pancreatic cancer screening. This has significant implications for research on the use of MUC1 in cancer detection.
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- 2013
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187. Cyclooxygenase-2 enzyme induces the expression of the α-2,3-sialyltransferase-3 (ST3Gal-I) in breast cancer.
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Sproviero D, Julien S, Burford B, Taylor-Papadimitriou J, and Burchell JM
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- Breast Neoplasms genetics, Cell Line, Tumor, Cyclooxygenase 2 genetics, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Sialyltransferases metabolism, beta-Galactoside alpha-2,3-Sialyltransferase, Breast Neoplasms enzymology, Cyclooxygenase 2 metabolism, Sialyltransferases genetics, Up-Regulation
- Abstract
Aberrant glycosylation is a common feature of malignant change. Changes in mucin-type O-linked glycosylation in breast cancer can result in the expression of truncated core 1-based sialylated glycans rather than the core 2-based glycans observed in normal mammary epithelium cells. This has been shown, in part, to be due to changes in the expression of glycosyltransferases, including the up-regulation of some sialyltransferases. Using the breast cancer cell line T47D, we have shown that PGE2, one of the final products of the cyclooxygenase-2 (COX-2) pathway, can induce the mRNA expression of the sialyltransferase α-2,3-sialyltransferase-3 (ST3Gal-I), resulting in increased sialyltransferase activity, demonstrated by a reduction in PNA lectin staining. Induction of COX-2 in the MDA-MB-231 breast cancer cell line also results in the increased expression of ST3Gal-I, leading to increased sialylation of the substrate of ST3Gal-I, core 1 Galβ1,3GalNAc. This effect on sialylation could be reversed by the selective COX-2 inhibitor celecoxib. The use of siRNA to knock down COX-2 and overexpression of COX-2 in MDA-MD-231 cells confirmed the involvement of COX-2 in the up-regulation of ST3Gal-I. Moreover, analysis of the expression of ST3Gal-I and COX-2 by 74 primary breast cancers showed a significant correlation between the two enzymes. COX-2 expression has been associated with a number of tumors, including breast cancer, where its expression is associated with poor prognoses. Thus, these results suggest the intriguing possibility that some of the malignant characteristics associated with COX-2 expression may be via the influence that COX-2 exerts on the glycosylation of tumor cells.
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- 2012
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188. Identification of new cancer biomarkers based on aberrant mucin glycoforms by in situ proximity ligation.
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Pinto R, Carvalho AS, Conze T, Magalhães A, Picco G, Burchell JM, Taylor-Papadimitriou J, Reis CA, Almeida R, Mandel U, Clausen H, Söderberg O, and David L
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- Adenocarcinoma, Mucinous metabolism, Adenocarcinoma, Mucinous pathology, Antigens, Tumor-Associated, Carbohydrate analysis, Antigens, Tumor-Associated, Carbohydrate metabolism, Breast pathology, CA-19-9 Antigen, Colon pathology, Fluorescent Antibody Technique, Gangliosides analysis, Gangliosides metabolism, Glycosylation, Humans, Immunohistochemistry, Lung pathology, Neoplasms pathology, Oligosaccharides analysis, Oligosaccharides metabolism, Sialyl Lewis X Antigen, Biomarkers, Tumor analysis, Mucin 5AC analysis, Mucin-1 analysis, Mucin-2 analysis, Mucin-6 analysis, Neoplasms diagnosis
- Abstract
Mucin glycoproteins are major secreted or membrane-bound molecules that, in cancer, show modifications in both the mucin proteins expression and in the O-glycosylation profile, generating some of the most relevant tumour markers in clinical use for decades. Thus far, the identification of these biomarkers has been based on the detection of either the protein or the O-glycan modifications. We therefore aimed to identify the combined mucin and O-glycan features, that is, specific glycoforms, in an attempt to increase specificity of these cancer biomarkers. Using in situ proximity ligation assays (PLA) based on existing monoclonal antibodies directed to MUC1, MUC2, MUC5AC and MUC6 mucins and to cancer-associated carbohydrate antigens Tn, Sialyl-Tn (STn), T, Sialyl-Le(a) (SLe(a)) and Sialyl-Le(x) (SLe(x)) we screened a series of 28 mucinous adenocarcinomas from different locations (stomach, ampulla of Vater, colon, lung, breast and ovary) to detect specific mucin glycoforms. We detected Tn/STn/SLe(a)/SLe(x)-MUC1 and STn/SLe(a)/SLe(x)-MUC2 glycoforms in ≥50% of the cases, with a variable distribution among organs. Some new glycoforms-T/SLe(a)-MUC2, STn/T/SLe(a) SLe(x)-MUC5AC and STn/T/SLe(a)/SLe(x)-MUC6-were identified for the first time in the present study in a variable percentage of cases from different organs. In conclusion, application of the PLA technique allowed sensitive detection of specific aberrant mucin glycoforms in cancer, increasing specificity to the use of antibodies either to the mucin protein backbone or to the O-glycan haptens alone., (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)
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- 2012
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189. Selectin ligand sialyl-Lewis x antigen drives metastasis of hormone-dependent breast cancers.
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Julien S, Ivetic A, Grigoriadis A, QiZe D, Burford B, Sproviero D, Picco G, Gillett C, Papp SL, Schaffer L, Tutt A, Taylor-Papadimitriou J, Pinder SE, and Burchell JM
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- Blotting, Western, Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Adhesion, Cell Line, Cell Line, Tumor, E-Selectin genetics, Female, Fucosyltransferases genetics, Fucosyltransferases metabolism, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Glycomics methods, Heparitin Sulfate metabolism, Human Umbilical Vein Endothelial Cells cytology, Human Umbilical Vein Endothelial Cells metabolism, Humans, Lewis X Antigen genetics, N-Acetylglucosaminyltransferases genetics, N-Acetylglucosaminyltransferases metabolism, Neoplasm Metastasis, Neoplasms, Hormone-Dependent genetics, Neoplasms, Hormone-Dependent pathology, Oligonucleotide Array Sequence Analysis, Receptors, Estrogen metabolism, Reverse Transcriptase Polymerase Chain Reaction, Sialyl Lewis X Antigen, Sialyltransferases genetics, Sialyltransferases metabolism, Sulfotransferases genetics, Sulfotransferases metabolism, beta-Galactoside alpha-2,3-Sialyltransferase, Breast Neoplasms metabolism, E-Selectin metabolism, Lewis X Antigen metabolism, Neoplasms, Hormone-Dependent metabolism
- Abstract
The glycome acts as an essential interface between cells and the surrounding microenvironment. However, changes in glycosylation occur in nearly all breast cancers, which can alter this interaction. Here, we report that profiles of glycosylation vary between ER-positive and ER-negative breast cancers. We found that genes involved in the synthesis of sialyl-Lewis x (sLe(x); FUT3, FUT4, and ST3GAL6) are significantly increased in estrogen receptor alpha-negative (ER-negative) tumors compared with ER-positive ones. SLe(x) expression had no influence on the survival of patients whether they had ER-negative or ER-positive tumors. However, high expression of sLe(x) in ER-positive tumors was correlated with metastasis to the bone where sLe(x) receptor E-selectin is constitutively expressed. The ER-positive ZR-75-1 and the ER-negative BT20 cell lines both express sLe(x) but only ZR-75-1 cells could adhere to activated endothelial cells under dynamic flow conditions in a sLe(x) and E-selectin-dependent manner. Moreover, L/P-selectins bound strongly to ER-negative MDA-MB-231 and BT-20 cell lines in a heparan sulfate (HS)-dependent manner that was independent of sLe(x) expression. Expression of glycosylation genes involved in heparan biosynthesis (EXT1 and HS3ST1) was increased in ER-negative tumors. Taken together, our results suggest that the context of sLe(x) expression is important in determining its functional significance and that selectins may promote metastasis in breast cancer through protein-associated sLe(x) and HS glycosaminoglycans.
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- 2011
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190. Transforming growth factor-β1 is constitutively secreted by Chinese hamster ovary cells and is functional in human cells.
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Beatson R, Sproviero D, Maher J, Wilkie S, Taylor-Papadimitriou J, and Burchell JM
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- Animals, CHO Cells, Cricetinae, Cricetulus, Enzyme-Linked Immunosorbent Assay, Gene Expression, Gene Expression Profiling, Humans, Immunologic Factors genetics, T-Lymphocytes drug effects, T-Lymphocytes immunology, Transforming Growth Factor beta1 genetics, Immunologic Factors metabolism, Immunologic Factors pharmacology, Transforming Growth Factor beta1 metabolism, Transforming Growth Factor beta1 pharmacology
- Abstract
Chinese hamster ovary (CHO) cells are widely used for the production of recombinant proteins for clinical use as well as academic research. They are particularly important for the production of glycoproteins where bacteria cannot be used. TGFβ1 is a potent cytokine highly conserved across species with multiple immunological and non-immunological effects. We have discovered that CHOK1, the CHO clone most commonly used by the pharmaceutical industry, constitutively secretes latent TGFβ1 and that this hamster TGFβ1 is active on human cells inducing profound immunological effects. As far as we are aware, the production of TGFβ1 by CHOK1 cells has not been reported before in the literature. As TGFβ1 exerts powerful and pleiotropic effects on diverse cell types, and as CHO cells are used to produce a large number of clinical and non-clinical products, our findings are highly relevant to studies that rely on recombinant proteins., (Copyright © 2011 Wiley Periodicals, Inc.)
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- 2011
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191. ST6GalNAc-I controls expression of sialyl-Tn antigen in gastrointestinal tissues.
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Marcos NT, Bennett EP, Gomes J, Magalhaes A, Gomes C, David L, Dar I, Jeanneau C, DeFrees S, Krustrup D, Vogel LK, Kure EH, Burchell J, Taylor-Papadimitriou J, Clausen H, Mandel U, and Reis CA
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- Animals, Antibodies, Monoclonal immunology, Antigens, Tumor-Associated, Carbohydrate, Base Sequence, CHO Cells, Cricetinae, Cricetulus, DNA Primers, Mice, Mice, Inbred BALB C, Sialyltransferases immunology, Gastrointestinal Tract immunology, Sialyltransferases metabolism
- Abstract
Sialyl-Tn is a simple mucin-type carbohydrate antigen aberrantly expressed in gastrointestinal adenocarcinomas and in the precursor lesion intestinal metaplasia. Sialyl-Tn tumour expression is an independent indicator of poor prognosis. We have previously shown in vitro that ST6GalNAc-I and ST6GalNAc-II sialyltransferases can synthesize sialyl-Tn. The aim of the present study was to establish whether ST6GalNAc-I is the major enzyme responsible for the expression of sialyl-Tn. We used a model of CHO-ldlD cells producing only MUC1-Tn glycoform and showed that ST6GalNAc-I is the key-enzyme leading to sialyl-Tn biosynthesis. We developed novel monoclonal antibodies specific for ST6GalNAc-I and evaluated its expression in gastrointestinal tissues. ST6GalNAc-I was detected in normal colon mucosa co-localized with O-acetylated sialyl-Tn. Expression was largely unaltered in colorectal adenocarcinomas. In contrast, we found that ST6GalNAc-I is weakly expressed in normal gastric mucosa, but over-expressed in intestinal metaplasia, co-localized with sialyl-Tn. In gastric carcinomas ST6GalNAc-I was also associated with sialyl-Tn, but with heterogeneous staining and partial co-localization. Our results showed ST6GalNAc-I as the major enzyme controlling the expression of cancer-associated sialyl-Tn antigen in gastrointestinal tissues.
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- 2011
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192. PLU-1/JARID1B/KDM5B is required for embryonic survival and contributes to cell proliferation in the mammary gland and in ER+ breast cancer cells.
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Catchpole S, Spencer-Dene B, Hall D, Santangelo S, Rosewell I, Guenatri M, Beatson R, Scibetta AG, Burchell JM, and Taylor-Papadimitriou J
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- Animals, Breast Neoplasms chemistry, Cell Line, Tumor, Cell Proliferation, Embryo, Mammalian physiology, Female, Humans, Jumonji Domain-Containing Histone Demethylases genetics, Male, Mice, Mice, Inbred C57BL, Nuclear Proteins genetics, Repressor Proteins genetics, Breast Neoplasms pathology, DNA-Binding Proteins physiology, Embryo, Mammalian cytology, Estrogen Receptor alpha analysis, Jumonji Domain-Containing Histone Demethylases physiology, Mammary Glands, Animal cytology, Nuclear Proteins physiology, Repressor Proteins physiology
- Abstract
The four members of the JARID1/KDM5 family of proteins, a sub-group of the larger ARID (AT rich DNA binding domain) family, have been shown to demethylate trimethylated lysine 4 on histone 3 (H3K4me3), a chromatin mark associated with actively transcribed genes. In some lower organisms a single homologue of JARID1 is found, and functions of the four proteins found in mice and humans may be specific or overlapping. To investigate the function of the Jarid1B protein we examined the effects of deletion of the gene in mice. Systemic knock out of Jarid1b resulted in early embryonic lethality, whereas mice not expressing the related Jarid1A gene are viable and fertile. A second mouse strain expressing a Jarid1b gene with the ARID domain deleted was viable and fertile but displayed a mammary phenotype, where terminal end bud development and side branching was delayed at puberty and in early pregnancy. Since development of terminal end buds are completely dependent on signalling from the estrogen receptor (ERα), we investigated the expression of a target gene (progesterone receptor) in the ∆ARID mouse and found levels to be reduced as compared to wild-type. JARID1B is widely expressed in ER+ breast cancers and breast cancer cell lines, and interaction with ERα was demonstrated by co-immunoprecipitations in cells transfected with tagged ERα and JARID1B genes. Down-regulation of expression of JARID1B using shRNAi in MCF-7 cells resulted in a dramatic decrease in E2 stimulated tumour growth in nude mice. The data demonstrate a specific role for Jarid1B in early embryonic development, in the development and differentiation of the normal mammary gland, and in estrogen induced growth of ER+ breast cancer.
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- 2011
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193. T cells reactive with HLA-A*0201 peptides from the histone demethylase JARID1B are found in the circulation of breast cancer patients.
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Coleman JA, Correa I, Cooper L, Bohnenkamp HR, Poulsom R, Burchell JM, and Taylor-Papadimitriou J
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- Adult, Antigens, Neoplasm immunology, Breast Neoplasms blood, Breast Neoplasms pathology, Cell Separation, Epitopes, T-Lymphocyte immunology, Female, Flow Cytometry, HLA-A2 Antigen, Histone Demethylases biosynthesis, Humans, In Situ Hybridization, Jumonji Domain-Containing Histone Demethylases biosynthesis, Neoplasm Staging, Nuclear Proteins biosynthesis, Peptides immunology, Repressor Proteins biosynthesis, Breast Neoplasms immunology, CD8-Positive T-Lymphocytes immunology, HLA-A Antigens immunology, Histone Demethylases immunology, Jumonji Domain-Containing Histone Demethylases immunology, Lymphocyte Activation, Neoplastic Cells, Circulating immunology, Nuclear Proteins immunology, Repressor Proteins immunology
- Abstract
The nuclear protein PLU-1/JARID1B/KDM5 is widely expressed in breast cancers while showing highly restricted expression in normal adult tissues. To investigate whether JARID1B is a potential target antigen for immunotherapy of breast cancer, we have analyzed the responses of CD8(+) T cells to JARID1B HLA-A*0201 peptides in vitro and used peptide multimers to detect the presence of JARID1B reactive T cells in the circulation of breast cancer patients. Peptides were selected using two web-based algorithms: criteria for inclusion being a high score in both prediction algorithms, and nonhomology with retinoblastoma binding protein-2 (RBP2/JARID1A/KDM5A). A 65-peptide panel was selected and assayed for binding strength by competition assay to obtain the IC(50). The immunogenicity in vitro of these peptides was assessed by T cell stimulation experiments, using autologous dendritic cells as APCs in the first rounds followed by autologous lymphoblasts. Fourteen of the peptides assayed produced cultures having >2% of the CD8(+) cells being IFN-γ(+) after 3-6 rounds of stimulation. An HLA-A*0201 cell line could activate the specific T cells if pulsed with peptide, but endogenous peptide levels were insufficient for activation. Nevertheless, multimer staining of circulating T cells from breast cancer patients showed a significantly higher percentage of multimer positive CD8(+) T cells, as compared to healthy adults for two of three JARID1B epitopes tested. One of these, peptide 73 (QLYALPCVL), was analyzed for memory phenotype, and found to have a significantly higher proportion of central memory T cells than the control group, demonstrating a previous exposure to the peptide., (Copyright © 2011 UICC.)
- Published
- 2011
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194. Autoantibodies to aberrantly glycosylated MUC1 in early stage breast cancer are associated with a better prognosis.
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Blixt O, Bueti D, Burford B, Allen D, Julien S, Hollingsworth M, Gammerman A, Fentiman I, Taylor-Papadimitriou J, and Burchell JM
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- Aged, Autoantibodies immunology, Biomarkers, Tumor immunology, Breast Neoplasms pathology, Cohort Studies, Epitopes immunology, Female, Glycopeptides immunology, Humans, Middle Aged, Prognosis, Autoantibodies blood, Biomarkers, Tumor blood, Breast Neoplasms diagnosis, Breast Neoplasms immunology, Mucin-1 immunology
- Abstract
Introduction: Detection of serum biomarkers for early diagnosis of breast cancer remains an important goal. Changes in the structure of O-linked glycans occur in all breast cancers resulting in the expression of glycoproteins that are antigenically distinct. Indeed, the serum assay widely used for monitoring disease progression in breast cancer (CA15.3), detects a glycoprotein (MUC1), but elevated levels of the antigen cannot be detected in early stage patients. However, since the immune system acts to amplify the antigenic signal, antibodies can be detected in sera long before the antigen. We have exploited the change in O-glycosylation to measure autoantibody responses to cancer-associated glycoforms of MUC1 in sera from early stage breast cancer patients., Methods: We used a microarray platform of 60mer MUC1 glycopeptides, to confirm the presence of autoantibodies to cancer associated glycoforms of MUC1 in a proportion of early breast cancer patients (54/198). Five positive sera were selected for detailed definition of the reactive epitopes using on chip glycosylation technology and a panel of glycopeptides based on a single MUC1 tandem repeat carrying specific glycans at specific sites. Based on these results, larger amounts of an extended repertoire of defined MUC1 glycopeptides were synthesised, printed on microarrays, and screened with sera from a large cohort of breast cancer patients (n = 395), patients with benign breast disease (n = 108) and healthy controls (n = 99). All sera were collected in the 1970s and 1980s and complete clinical follow-up of breast cancer patients is available., Results: The presence and level of autoantibodies was significantly higher in the sera from cancer patients compared with the controls, and a highly significant correlation with age was observed. High levels of a subset of autoantibodies to the core3MUC1 (GlcNAcβ1-3GalNAc-MUC1) and STnMUC1 (NeuAcα2,6GalNAc-MUC1) glycoforms were significantly associated with reduced incidence and increased time to metastasis., Conclusions: Autoantibodies to specific cancer associated glycoforms of MUC1 are found more frequently and at higher levels in early stage breast cancer patients than in women with benign breast disease or healthy women. Association of strong antibody response with reduced rate and delay in metastases suggests that autoantibodies can affect disease progression.
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- 2011
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195. Over-expression of ST3Gal-I promotes mammary tumorigenesis.
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Picco G, Julien S, Brockhausen I, Beatson R, Antonopoulos A, Haslam S, Mandel U, Dell A, Pinder S, Taylor-Papadimitriou J, and Burchell J
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- Animals, Antigens, Polyomavirus Transforming genetics, Blotting, Western, Female, Galactose metabolism, Glycosylation, Humans, Immunoprecipitation, Lactation metabolism, Mammary Glands, Animal enzymology, Mammary Neoplasms, Experimental genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mucin-1 genetics, N-Acetylneuraminic Acid metabolism, Pregnancy, Promoter Regions, Genetic genetics, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Sialyltransferases genetics, beta-Galactoside alpha-2,3-Sialyltransferase, Mammary Neoplasms, Experimental enzymology, Mammary Neoplasms, Experimental pathology, Sialyltransferases metabolism
- Abstract
Changes in glycosylation are common in malignancy, and as almost all surface proteins are glycosylated, this can dramatically affect the behavior of tumor cells. In breast carcinomas, the O-linked glycans are frequently truncated, often as a result of premature sialylation. The sialyltransferase ST3Gal-I adds sialic acid to the galactose residue of core 1 (Galbeta1,3GalNAc) O-glycans and this enzyme is over-expressed in breast cancer resulting in the expression of sialylated core 1 glycans. In order to study the role of ST3Gal-I in mammary tumor development, we developed transgenic mice that over-express the sialyltransferase under the control of the human membrane-bound mucin 1 promoter. These mice were then crossed with PyMT mice that spontaneously develop mammary tumors. As expected, ST3Gal-I transgenic mice showed increased activity and expression of the enzyme in the pregnant and lactating mammary glands, the stomach, lungs and intestine. Although no obvious defects were observed in the fully developed mammary gland, when these mice were crossed with PyMT mice, a highly significant decrease in tumor latency was observed compared to the PyMT mice on an identical background. These results indicate that ST3Gal-I is acting as a tumor promoter in this model of breast cancer. This, we believe, is the first demonstration that over-expression of a glycosyltransferase involved in mucin-type O-linked glycosylation can promote tumorigenesis.
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- 2010
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196. MUC1 immunotherapy.
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Beatson RE, Taylor-Papadimitriou J, and Burchell JM
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- Animals, Antibodies, Monoclonal immunology, Antibodies, Monoclonal therapeutic use, Cancer Vaccines immunology, Cancer Vaccines therapeutic use, Dendritic Cells immunology, Glycosylation, Humans, Immunotherapy trends, Mucin-1 metabolism, Neoplasms immunology, Neoplasms metabolism, T-Lymphocytes immunology, Immunotherapy methods, Mucin-1 immunology, Neoplasms therapy
- Abstract
The overexpression and aberrant glycosylation of MUC1 is associated with a wide variety of cancers, making it an ideal target for immunotherapeutic strategies. This review highlights the main avenues of research in this field, focusing on adenocarcinomas, from the preclinical to clinical; the problems and possible solutions associated with each approach; and speculates on the direction of MUC1 immunotherapeutic research over the next 5-10 years.
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- 2010
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197. Cancer biomarkers defined by autoantibody signatures to aberrant O-glycopeptide epitopes.
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Wandall HH, Blixt O, Tarp MA, Pedersen JW, Bennett EP, Mandel U, Ragupathi G, Livingston PO, Hollingsworth MA, Taylor-Papadimitriou J, Burchell J, and Clausen H
- Subjects
- Antigen Presentation physiology, Autoantibodies blood, Breast Neoplasms blood, Breast Neoplasms immunology, Carcinoma blood, Carcinoma immunology, Case-Control Studies, Clinical Trials, Phase I as Topic, Enzyme-Linked Immunosorbent Assay methods, Epitope Mapping methods, Female, Humans, Immunization, Male, Models, Biological, Mucin-1 chemistry, Mucin-1 immunology, Ovarian Neoplasms blood, Ovarian Neoplasms immunology, Peptide Library, Prostatic Neoplasms blood, Prostatic Neoplasms immunology, Protein Array Analysis instrumentation, Protein Array Analysis methods, Autoantibodies analysis, Biomarkers, Tumor analysis, Biomarkers, Tumor immunology, Epitopes analysis, Glycopeptides immunology
- Abstract
Autoantibodies to cancer antigens hold promise as biomarkers for early detection of cancer. Proteins that are aberrantly processed in cancer cells are likely to present autoantibody targets. The extracellular mucin MUC1 is overexpressed and aberrantly glycosylated in many cancers; thus, we evaluated whether autoantibodies generated to aberrant O-glycoforms of MUC1 might serve as sensitive diagnostic biomarkers for cancer. Using an antibody-based glycoprofiling ELISA assay, we documented that aberrant truncated glycoforms were not detected in sera of cancer patients. An O-glycopeptide microarray was developed that detected IgG antibodies to aberrant O-glycopeptide epitopes in patients vaccinated with a keyhole limpet hemocyanin-conjugated truncated MUC1 peptide. We detected cancer-associated IgG autoantibodies in sera from breast, ovarian, and prostate cancer patients against different aberrent O-glycopeptide epitopes derived from MUC1. These autoantibodies represent a previously unaddressed source of sensitive biomarkers for early detection of cancer. The methods we have developed for chemoenzymatic synthesis of O-glycopeptides on microarrays may allow for broader mining of the entire cancer O-glycopeptidome.
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- 2010
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198. Sialyl-Tn vaccine induces antibody-mediated tumour protection in a relevant murine model.
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Julien S, Picco G, Sewell R, Vercoutter-Edouart AS, Tarp M, Miles D, Clausen H, Taylor-Papadimitriou J, and Burchell JM
- Subjects
- Animals, Cell Line, Tumor, Disease Models, Animal, Hemocyanins immunology, Immunotherapy, Mice, Mice, Inbred BALB C, Mucin-1 immunology, Neoplasms metabolism, Neoplasms pathology, Survival Rate, Antibodies immunology, Antigens, Tumor-Associated, Carbohydrate immunology, Antigens, Tumor-Associated, Carbohydrate metabolism, Biomarkers, Tumor immunology, Biomarkers, Tumor metabolism, Neoplasms immunology, Vaccines immunology
- Abstract
Changes in the composition of glycans added to glycoproteins and glycolipids are characteristic of the change to malignancy. Sialyl-Tn (STn) is expressed by 25-30% of breast carcinomas but its expression on normal tissue is highly restricted. Sialyl-Tn is an O-linked disaccharide that can be carried on various glycoproteins. One such glycoprotein MUC1 is expressed by the vast majority of breast carcinomas. Both STn and MUC1 have been considered as targets for immunotherapy of breast cancer patients. Here we used different immunogens to target STn in an MUC1 transgenic mouse model of tumour challenge. We show that synthetic STn coupled to keyhole limpet haemocyanin (Theratope), induced antibodies to STn that recognised the glycan carried on a number of glycoproteins and in these mice a significant delay in tumour growth was observed. The protection was dependent on STn being expressed by the tumour and was antibody mediated. Affinity chromatography of the STn-expressing tumour cell line, followed by mass spectrometry, identified osteopontin as a novel STn-carrying glycoprotein which was highly expressed by the tumours. These results suggest that if antibodies can be induced to a number of targets expressed by the tumour cells, a humoral response can be effective in controlling tumour growth.
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- 2009
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199. Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor.
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Wilkie S, Picco G, Foster J, Davies DM, Julien S, Cooper L, Arif S, Mather SJ, Taylor-Papadimitriou J, Burchell JM, and Maher J
- Subjects
- Carbohydrate Metabolism, Cells, Cultured, Cytotoxicity, Immunologic immunology, Homeodomain Proteins immunology, Humans, Immunoglobulin D immunology, Mucin-1 genetics, Neoplasms genetics, Neoplasms immunology, Protein Binding, Protein Engineering, Receptors, Antigen genetics, Mucin-1 immunology, Mucin-1 metabolism, Neoplasms metabolism, Receptors, Antigen immunology, Receptors, Antigen metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
MUC1 is a highly attractive immunotherapeutic target owing to increased expression, altered glycosylation, and loss of polarity in >80% of human cancers. To exploit this, we have constructed a panel of chimeric Ag receptors (CAR) that bind selectively to tumor-associated MUC1. Two parameters proved crucial in optimizing the CAR ectodomain. First, we observed that the binding of CAR-grafted T cells to anchored MUC1 is subject to steric hindrance, independent of glycosylation status. This was overcome by insertion of the flexible and elongated hinge found in immunoglobulins of the IgD isotype. Second, CAR function was highly dependent upon strong binding capacity across a broad range of tumor-associated MUC1 glycoforms. This was realized by using an Ab-derived single-chain variable fragment (scFv) cloned from the HMFG2 hybridoma. To optimize CAR signaling, tripartite endodomains were constructed. Ultimately, this iterative design process yielded a potent receptor termed HOX that contains a fused CD28/OX40/CD3zeta endodomain. HOX-expressing T cells proliferate vigorously upon repeated encounter with soluble or membrane-associated MUC1, mediate production of proinflammatory cytokines (IFN-gamma and IL-17), and elicit brisk killing of MUC1(+) tumor cells. To test function in vivo, a tumor xenograft model was derived using MDA-MB-435 cells engineered to coexpress MUC1 and luciferase. Mice bearing an established tumor were treated i.p. with a single dose of engineered T cells. Compared with control mice, this treatment resulted in a significant delay in tumor growth as measured by serial bioluminescence imaging. Together, these data demonstrate for the first time that the near-ubiquitous MUC1 tumor Ag can be targeted using CAR-grafted T cells.
- Published
- 2008
- Full Text
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200. Immunisation with 'naïve' syngeneic dendritic cells protects mice from tumour challenge.
- Author
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Grimshaw MJ, Papazisis K, Picco G, Bohnenkamp H, Noll T, Taylor-Papadimitriou J, and Burchell J
- Subjects
- Animals, B-Lymphocytes immunology, B-Lymphocytes metabolism, Cell Line, Female, Flow Cytometry, Immunization, Interferon-gamma metabolism, Interleukin-4 metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mucin-1 physiology, Neoplasms, Experimental immunology, Neoplasms, Experimental pathology, Phenotype, Spleen cytology, Spleen immunology, Spleen metabolism, Survival Rate, T-Lymphocytes immunology, T-Lymphocytes metabolism, T-Lymphocytes, Cytotoxic, Dendritic Cells immunology, Immunotherapy, Neoplasms, Experimental therapy
- Abstract
Dendritic cells (DCs) 'pulsed' with an appropriate antigen may elicit an antitumour immune response in mouse models. However, while attempting to develop a DC immunotherapy protocol for the treatment of breast cancer based on the tumour-associated MUC1 glycoforms, we found that unpulsed DCs can affect tumour growth. Protection from RMA-MUC1 tumour challenge was achieved in C57Bl/6 MUC1 transgenic mice by immunising with syngeneic DCs pulsed with a MUC1 peptide. However, unpulsed DCs gave a similar level of protection, making it impossible to evaluate the effect of immunisation of mice with DCs pulsed with the specific peptide. Balb/C mice could also be protected from tumour challenge by immunisation with unpulsed DCs prior to challenge with murine mammary tumour cells (410.4) or these cells transfected with MUC1 (E3). Protection was achieved with as few as three injections of 50,000 naïve DCs per mouse per week, was not dependent on injection route, and was not specific to cell lines expressing human MUC1. However, the use of Rag2-knockout mice demonstrated that the adaptive immune response was required for tumour rejection. Injection of unpulsed DCs into mice bearing the E3 tumour slowed tumour growth. In vitro, production of IFN-gamma and IL-4 was increased in splenic cells isolated from mice immunised with DCs. Depleting CD4 T cells in vitro partially decreased cytokine production by splenocytes, but CD8 depletion had no effect. This paper shows that naïve syngeneic DCs may induce an antitumour immune response and has implications for DC immunotherapy preclinical and clinical trials.
- Published
- 2008
- Full Text
- View/download PDF
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