Open AccessJournal Article
Tolerance and immunity to MUC1 in a human MUC1 transgenic murine model
Richard M. Tempero,Keita Morikane,Michelle L. VanLith,Sandra J. Gendler,Michael A. Hollingsworth +4 more
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TLDR
Data suggest that endogenous expression of MUC1 protein by M UC1 transgenic mice induces T-cell tolerance to stimulation by MUC2, and will facilitate the investigation of anti-MUC1 immunotherapy formulations.Abstract:
The human epithelial mucin, MUC1, is a large transmembrane glycoprotein that is expressed on most simple epithelia. It is overexpressed and aberrantly glycosylated on many human epithelial tumors, including more than 90% of human breast cancers. MUC1 is of interest as an immunotherapy target because patients with breast, ovarian, and pancreatic cancers have T lymphocytes in their tumor-draining lymph nodes that can be induced to recognize and lyse MUC1-expressing tumor cells. We have produced a transgenic mouse model that expresses the human MUC1 molecule on an inbred C57Bl/6 background to investigate the effect of endogenous expression of MUC1 on the ability of mice to generate antitumor immunity to MUC1-expressing tumors. Transgenic mice expressed the human transgene in a pattern and level consistent with that observed in humans. Transgenic mice were tolerant to stimulation by MUC1 as evidenced by the ability of MUC1-expressing tumor cells to grow in these mice, whereas MUC1-expressing cells were eliminated from wild-type mice. Moreover, transgenic mice immunized with MUC1 peptides failed to exhibit immunoglobulin class switching to the IgG subtypes. These data suggest that endogenous expression of MUC1 protein by MUC1 transgenic mice induces T-cell tolerance to stimulation by MUC1. The transgenic mice will provide a useful model to investigate the mechanisms that regulate immunological tolerance to tumor antigens and will facilitate the investigation of anti-MUC1 immunotherapy formulations.read more
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Assessing the Effects of Concurrent versus Sequential Cisplatin/Radiotherapy on Immune Status in Lung Tumor-Bearing C57BL/6 Mice
Chiao Jung Kao,Gregory T. Wurz,Yi Chen Lin,Daniel P. Vang,Stephen M Griffey,Michael Wolf,Michael W. DeGregorio +6 more
TL;DR: The results showed that sequential chemoradiotherapy had equivalent antitumor activity as concurrent therapy, however, sequential cisplatin/radiotherapy resulted in significant differences in several immune response biomarkers, including regulatory T cells, miR-29c, expression of costimulatory molecule CD28, and serum IFNγ.
Journal ArticleDOI
Local effects of regulatory T cells in MUC1 transgenic mice potentiate growth of MUC1 expressing tumor cells in vivo.
Daisuke Sugiura,Kaori Denda-Nagai,Mitsuyo Takashima,Ryuichi Murakami,Shigenori Nagai,Kazuyoshi Takeda,Tatsuro Irimura +6 more
TL;DR: It is shown that numbers of Treg cells in MUC1-expressing tumors were greater in M.UC1.Tg mice than in control C57BL/6 (B6) mice, and that the growth of tumor cells expressing Muc1, but not that of control cells, in M UC1.
Book ChapterDOI
Targeted Immunotherapy Designed to Treat MUC1-Expressing Solid Tumour.
TL;DR: This chapter will describe studies done with the antigen MUC1, which has been tested clinically as well as several approaches to antigen-specific immunotherapy of cancer.
Journal ArticleDOI
Induction of Antitumor Immunity by Dendritic Cells Loaded with Membrane-Translocating Mucin 1 Peptide Antigen
Saho Kobukai,Gert-Jan Kremers,Jared G. Cobb,Richard A. Baheza,Jingping Xie,Alex Kuley,Meiying Zhu,Wellington Pham +7 more
TL;DR: In summary, enhanced antigen uptake using an MPA(11)P delivery molecule improves cell therapy and is described as a cell-penetrating mucin 1 (MUC1) antigen and its immunotherapeutic potential against tumors.
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Therapeutic MUC1-Based Cancer Vaccine Expressed in Flagella-Efficacy in an Aggressive Model of Breast Cancer
Machluf Nathalie,Arnon Ruth +1 more
TL;DR: Recombinant flagella carrying a 25-residue fragment of MUC1, induced the most effective response, as evidenced by a significant reduction of both the size and growth rate of the tumor as well as by the lower number of metastases, and expanding life span of vaccinated mice.
References
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Journal ArticleDOI
Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes
David Nemazee,Kurt Bürki +1 more
TL;DR: B-cell tolerance in transgenic mice using genes for IgM anti-H–2k MHC class I antibody is studied and it is suggested that very large numbers of autospecific B cells can be controlled by clonal deletion.
Journal ArticleDOI
Molecular cloning and expression of human Tumor-associated Polymorphic Epithelial Mucin
Sandra Gendler,Carole A. Lancaster,Joyce Taylor-Papadimitriou,Trevor Duhig,Nigel Peat,Joy Burchell,Lucy Pemberton,El-Nasir Lalani,David Wilson +8 more
TL;DR: The full sequence for PEM, as deduced from cDNA sequences, is reported, with length variations in the tandem repeat result in PEM being an expressed variable number tandem repeat locus.
Journal ArticleDOI
Epithelial Mucin Genes
TL;DR: Functional studies are in progress both in vitro using cDNAs and cell lines and in vivo utilizing mutant mice in which a particular mucin gene has been inactivated or overexpressed to help determine whether the functions of mucins are restricted to protection and lubrication, or if they are involved in the adhesion of tumor cells to other cells or tissue components or in modulation of the immune system.
Journal ArticleDOI
A highly immunogenic region of a human polymorphic epithelial mucin expressed by carcinomas is made up of tandem repeats.
TL;DR: It is shown here that all three antibodies react with a synthetic peptide with an amino acid sequence corresponding to that predicted by the tandem repeat, allowing a directed approach to the development of tumor-specific antibodies using synthetic peptides as immunogens.
Journal ArticleDOI
MUC1, the renaissance molecule.
TL;DR: Recent discoveries that suggest that MUC1 may be a multifunctional protein, located on the surfaces of cells as a sensor of the environment, poised to signal to the interior when things go awry are highlighted.