title: Blocking retinoic acid receptor-α enhances the efficacy of a dendritic cell vaccine against tumours by suppressing the induction of regulatory T cells.
abstract: The immune system has evolved regulatory mechanisms to control immune responses to self-antigens. Regulatory T (Treg) cells play a pivotal role in maintaining immune tolerance, but tumour growth is associated with local immunosuppression, which can subvert effector immune responses. Indeed, the induction and recruitment of Treg cells by tumours is a major barrier in the development of effective immunotherapeutics and vaccines against cancer. Retinoic acid (RA) has been shown to promote conversion of naïve T cells into Treg cells. This study addresses the hypothesis that blocking RA receptor alpha (RARα) may enhance the efficacy of a tumour vaccine by inhibiting the induction of Treg cells. We found that RA significantly enhanced TGF-β-induced expression of Foxp3 on naïve and committed T cells in vitro and that this was blocked by an antagonist of RARα (RARi). In addition, RARi significantly suppressed TGF-β and IL-10 and enhanced IL-12 production by dendritic cells (DC) in response to killed tumour cells or TLR agonists. Furthermore, RARi augmented the efficacy of an antigen-pulsed and TLR-activated DC vaccine, significantly attenuating growth of B16 tumours in vivo and enhancing survival of mice. This protective effect was associated with significant reduction in tumour-infiltrating FoxP3(+) and IL-10(+) Treg cells and a corresponding increase in tumour-infiltrating CD4(+) and CD8(+) T cells that secreted IFN-γ. Our findings demonstrate that RARα is an important target for the development of effective anti-tumour immunotherapeutics and for improving the efficacy of cancer vaccines.
authors: Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, 152-160 Pearse St, Dublin 2, Ireland.
authors: Karen C
authors: KC
authors: Galvin
authors: Lydia
authors: L
authors: Dyck
authors: Neil A
authors: NA
authors: Marshall
authors: Anna M
authors: AM
authors: Stefanska
authors: Kevin P
authors: KP
authors: Walsh
authors: Barry
authors: B
authors: Moran
authors: Sarah C
authors: SC
authors: Higgins
authors: Lara S
authors: LS
authors: Dungan
authors: Kingston H G
authors: KH
authors: Mills
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007167:Immunotherapy; D016753:Interleukin-10 / Q000037:antagonists & inhibitors; D018664:Interleukin-12 / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D000072482:Retinoic Acid Receptor alpha; D017634:Self Tolerance; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors
chemical_list: D019496:Cancer Vaccines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12; D000444:Aldehyde Dehydrogenase
references: Mech Dev. 2000 Oct;97(1-2):227-30
references: 11025231
references: J Immunol. 2006 Jul 15;177(2):896-904
references: 16818744
references: Immunology. 2010 Dec;131(4):556-69
references: 20722761
references: Immunity. 2011 Mar 25;34(3):435-47
references: 21419664
references: J Exp Med. 2007 Aug 6;204(8):1775-85
references: 17620362
references: Springer Semin Immunopathol. 2005 Jan;26(3):289-307
references: 15609003
references: J Clin Oncol. 2005 Sep 1;23(25):6043-53
references: 16087944
references: Adv Drug Deliv Rev. 2006 Oct 1;58(8):948-61
references: 17070961
references: Prog Nucleic Acid Res Mol Biol. 1999;63:139-88
references: 10506831
references: Cancer Res. 1999 Jul 1;59(13):3128-33
references: 10397255
references: Cancer Immun. 2009 Apr 02;9:3
references: 19338264
references: Science. 2007 Jul 13;317(5835):256-60
references: 17569825
references: N Engl J Med. 2010 Jul 29;363(5):411-22
references: 20818862
references: J Exp Med. 2007 Aug 6;204(8):1757-64
references: 17620361
references: J Immunol. 2010 Jun 15;184(12):6799-806
references: 20488794
references: Blood. 2008 Feb 1;111(3):1013-20
references: 17951529
references: Clin Cancer Res. 2007 Mar 15;13(6):1810-5
references: 17363537
references: Eur J Immunol. 2007 Sep;37(9):2396-9
references: 17694576
references: Nat Immunol. 2007 Oct;8(10):1086-94
references: 17873879
references: J Immunol. 2008 Mar 15;180(6):3797-806
references: 18322186
references: J Exp Med. 2001 Jan 15;193(2):233-8
references: 11208863
references: Nature. 2011 Mar 10;471(7337):220-4
references: 21307853
references: J Immunol. 2011 Feb 15;186(4):1934-42
references: 21220692
references: J Dermatolog Treat. 2011 Dec;22(6):353-8
references: 21781010
references: Cancer Immunol Immunother. 2012 Mar;61(3):425-31
references: 22193988
references: Cancer Res. 2012 Feb 1;72(3):581-91
references: 22158905
references: Mol Cell Biol. 2002 Mar;22(5):1446-59
references: 11839811
references: Oncogene. 2008 Jan 7;27(2):168-80
references: 18176598
references: J Exp Med. 2002 May 20;195(10):1279-88
references: 12021308
references: J Exp Med. 2000 Dec 4;192(11):1535-44
references: 11104796
references: J Nutr. 1987 May;117(5):857-65
references: 3495650
references: Annu Rev Immunol. 2004;22:531-62
references: 15032588