| Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay. | |
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MedLine Citation:
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PMID: 20463739 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The main reason why tumours are not controlled by the immune system is that, unlike pathogens, they do not express potent tumour rejection antigens (TRAs). Tumour vaccination aims at stimulating a systemic immune response targeted to, mostly weak, antigens expressed in the disseminated tumour lesions. Main challenges in developing effective vaccination protocols are the identification of potent and broadly expressed TRAs and effective adjuvants to stimulate a robust and durable immune response. Here we describe an alternative approach in which the expression of new, and thereby potent, antigens are induced in tumour cells by inhibiting nonsense-mediated messenger RNA decay (NMD). Small interfering RNA (siRNA)-mediated inhibition of NMD in tumour cells led to the expression of new antigenic determinants and their immune-mediated rejection. In subcutaneous and metastatic tumour models, tumour-targeted delivery of NMD factor-specific siRNAs conjugated to oligonucleotide aptamer ligands led to significant inhibition of tumour growth that was superior to that of vaccination with granulocyte-macrophage colony-stimulating factor (GM-CSF)-expressing irradiated tumour cells, and could be further enhanced by co-stimulation. Tumour-targeted NMD inhibition forms the basis of a simple, broadly useful, and clinically feasible approach to enhance the antigenicity of disseminated tumours leading to their immune recognition and rejection. The cell-free chemically synthesized oligonucleotide backbone of aptamer-siRNAs reduces the risk of immunogenicity and enhances the feasibility of generating reagents suitable for clinical use. |
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Authors:
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Fernando Pastor; Despina Kolonias; Paloma H Giangrande; Eli Gilboa |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Nature Volume: 465 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-13 Completed Date: 2010-06-15 Revised Date: 2012-03-01 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 227-30 Citation Subset: IM |
Affiliation:
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Department of Microbiology & Immunology, Dodson Interdisciplinary Immunotherapy Institute, University of Miami Miller School of Medicine Miami, Florida 33134, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antigens, Neoplasm / genetics*, immunology* Aptamers, Nucleotide / genetics Cancer Vaccines / genetics, immunology, metabolism Carrier Proteins / genetics Cell Line, Tumor Chickens / genetics Colonic Neoplasms / genetics*, immunology*, pathology Gene Expression Regulation, Neoplastic Granulocyte-Macrophage Colony-Stimulating Factor / genetics, metabolism Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Nude Neoplasm Transplantation RNA Interference RNA Stability / genetics* RNA, Small Interfering / genetics*, therapeutic use Xenograft Model Antitumor Assays |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA138503-04/CA/NCI NIH HHS; R01 CA151857-02/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigens, Neoplasm; 0/Aptamers, Nucleotide; 0/Cancer Vaccines; 0/Carrier Proteins; 0/RNA, Small Interfering; 0/Upf2 protein, mouse; 83869-56-1/Granulocyte-Macrophage Colony-Stimulating Factor |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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