title: Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay.
abstract: 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.
authors.affiliation: Department of Microbiology & Immunology, Dodson Interdisciplinary Immunotherapy Institute, University of Miami Miller School of Medicine Miami, Florida 33134, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Pastor
authors.forename: Despina
authors.initials: D
authors.lastname: Kolonias
authors.forename: Paloma H
authors.initials: PH
authors.lastname: Giangrande
authors.forename: Eli
authors.initials: E
authors.lastname: Gilboa
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology*; D052157:Aptamers, Nucleotide / Q000235:genetics; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002645:Chickens / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D034622:RNA Interference; D020871:RNA Stability / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics* / Q000627:therapeutic use; D016601:RNA-Binding Proteins; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D052157:Aptamers, Nucleotide; D019496:Cancer Vaccines; D002352:Carrier Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C529977:Upf2 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
references.citation: Nat Rev Genet. 2008 Sep;9(9):699-712
references.pmid: 18679436
references.citation: Nat Rev Immunol. 2002 Apr;2(4):227-38
references.pmid: 12001994
references.citation: Cancer Res. 2002 May 1;62(9):2447-54
references.pmid: 11980631
references.citation: Mol Ther. 2006 Sep;14(3):351-60
references.pmid: 16807116
references.citation: Biochim Biophys Acta. 2008 Sep;1779(9):538-49
references.pmid: 18657639
references.citation: Immunol Rev. 2008 Apr;222:287-98
references.pmid: 18364009
references.citation: Cell. 2006 Feb 24;124(4):783-801
references.pmid: 16497588
references.citation: J Clin Invest. 2006 Jul;116(7):1935-45
references.pmid: 16778987
references.citation: Nat Genet. 2004 Oct;36(10):1073-8
references.pmid: 15448691
references.citation: Cancer Res. 2002 Jul 15;62(14):4029-33
references.pmid: 12124337
references.citation: Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3539-43
references.pmid: 8097319
references.citation: Semin Immunol. 2008 Oct;20(5):276-85
references.pmid: 18684640
references.citation: Immunity. 2008 Sep 19;29(3):372-83
references.pmid: 18799145
references.citation: Annu Rev Med. 2005;56:555-83
references.pmid: 15660527
references.citation: Nat Rev Cancer. 2004 May;4(5):401-11
references.pmid: 15122211
references.citation: FEBS Lett. 2007 Jun 19;581(15):2845-53
references.pmid: 17531985
references.citation: Nat Biotechnol. 2005 Apr;23(4):457-62
references.pmid: 15778705
references.citation: Cell. 1994 Jan 14;76(1):17-27
references.pmid: 8287475
references.citation: J Exp Med. 1999 Aug 2;190(3):355-66
references.pmid: 10430624
references.citation: PLoS One. 2008 Jul 09;3(7):e2583
references.pmid: 18612427
references.citation: Cancer Immunol Immunother. 2005 Mar;54(3):187-207
references.pmid: 15309328
references.citation: Nat Rev Mol Cell Biol. 2004 Feb;5(2):89-99
references.pmid: 15040442
references.citation: Mol Ther. 2007 May;15(5):938-45
references.pmid: 17311008
references.citation: Hum Mol Genet. 1999;8(10):1893-900
references.pmid: 10469842
references.citation: J Exp Med. 2003 Aug 18;198(4):569-80
references.pmid: 12925674
references.citation: Immunity. 1999 Sep;11(3):263-70
references.pmid: 10514004
references.citation: Mol Cell Biol. 2006 Feb;26(4):1272-87
references.pmid: 16449641
references.citation: J Clin Invest. 2008 Jan;118(1):376-86
references.pmid: 18060045
references.citation: J Biol Chem. 1995 Jun 9;270(23):13581-4
references.pmid: 7775406