title: Disruption of TGF-beta signaling prevents the generation of tumor-sensitized regulatory T cells and facilitates therapeutic antitumor immunity.
abstract: Regulatory T (Treg) cells represent a major roadblock to the induction of antitumor immunity through vaccine approaches. TGF-beta is a cytokine implicated in the generation and maintenance of Treg cells, as well as in their suppressive function. These experiments examined whether the generation of tumor-sensitized Treg cells was TGF-beta dependent and evaluated whether TGF-beta produced by Treg cells blocked the priming of tumor-specific T cells in vaccinated reconstituted lymphopenic mice. We show that tumor-sensitized Treg cells (CD25(+)/FoxP3(+)) obtained from tumor-bearing mice block the generation of tumor-specific T cells in reconstituted lymphopenic mice. Strikingly, this suppression is absent if tumor-sensitized Treg cells are acquired from tumor-bearing mice expressing the dominant-negative TGFbetaRII in T cells. This loss of suppression was a result of the crucial role of TGF-beta in generating tumor-sensitized Treg cells, and not due to the insensitivity of naive or tumor-primed effector T cells to the direct suppressive influence of TGF-beta. We conclude that blocking TGF-beta in a tumor-bearing host can inhibit the induction of highly suppressive tumor-sensitized Treg cells. These data suggest that an integrative strategy combining "up-front" Treg cell ablation followed by vaccination and TGF-beta blockade may limit generation of new tumor-sensitized Treg cells and improve the generation of therapeutic immune responses in patients with cancer.
authors.affiliation: Laboratory of Molecular and Tumor Immunology, Robert W Franz Cancer Research Center, Earle A Chiles Research Institute, Providence Cancer Center and Providence Portland Medical Center, Portland, OR 97213, USA.
authors.forename: Ulf
authors.initials: U
authors.lastname: Petrausch
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Jensen
authors.forename: Christopher
authors.initials: C
authors.lastname: Twitty
authors.forename: Christian H
authors.initials: CH
authors.lastname: Poehlein
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Haley
authors.forename: Edwin B
authors.initials: EB
authors.lastname: Walker
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Fox
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology; D002478:Cells, Cultured; D007109:Immunity; D016219:Immunotherapy, Adoptive / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D016212:Transforming Growth Factor beta
references.citation: J Exp Med. 2004 May 17;199(10):1401-8
references.pmid: 15148338
references.citation: Cancer. 1999 Feb 1;85(3):554-61
references.pmid: 10091729
references.citation: Nat Rev Immunol. 2007 Jun;7(6):443-53
references.pmid: 17525753
references.citation: Cancer Epidemiol Biomarkers Prev. 1998 Jun;7(6):497-504
references.pmid: 9641494
references.citation: Clin Cancer Res. 2005 Dec 1;11(23):8326-31
references.pmid: 16322292
references.citation: J Exp Med. 1996 Aug 1;184(2):387-96
references.pmid: 8760792
references.citation: J Exp Med. 2005 Mar 7;201(5):737-46
references.pmid: 15753207
references.citation: J Immunol. 2005 Feb 15;174(4):1783-6
references.pmid: 15699103
references.citation: Eur J Immunol. 2003 Aug;33(8):2123-32
references.pmid: 12884286
references.citation: Clin Cancer Res. 2008 May 15;14(10):3156-67
references.pmid: 18483384
references.citation: Nat Rev Immunol. 2003 Aug;3(8):630-41
references.pmid: 12974478
references.citation: Blood. 2006 Jan 15;107(2):628-36
references.pmid: 16179369
references.citation: Oligonucleotides. 2007 Summer;17(2):201-12
references.pmid: 17638524
references.citation: Nature. 2006 May 11;441(7090):235-8
references.pmid: 16648838
references.citation: Science. 1993 May 28;260(5112):1335-8
references.pmid: 8388126
references.citation: Immunol Rev. 2006 Oct;213:131-45
references.pmid: 16972901
references.citation: Prog Exp Tumor Res. 1970;13:1-27
references.pmid: 4921480
references.citation: J Immunol. 2004 May 1;172(9):5149-53
references.pmid: 15100250
references.citation: Nat Immunol. 2005 Dec;6(12):1219-27
references.pmid: 16244650
references.citation: J Clin Oncol. 2006 Oct 10;24(29):4721-30
references.pmid: 16966690
references.citation: Cancer Res. 2006 Mar 15;66(6):3294-302
references.pmid: 16540683
references.citation: J Immunol. 2004 May 15;172(10):6003-10
references.pmid: 15128783
references.citation: Immunity. 2006 Jun;24(6):677-688
references.pmid: 16782025
references.citation: J Exp Med. 2002 Jun 3;195(11):1499-505
references.pmid: 12045248
references.citation: J Immunol. 2005 Sep 1;175(5):3025-32
references.pmid: 16116190
references.citation: Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5262-70
references.pmid: 17875754
references.citation: J Immunol. 2007 Feb 15;178(4):2018-27
references.pmid: 17277105
references.citation: J Clin Invest. 2005 Dec;115(12):3623-33
references.pmid: 16308572
references.citation: Cancer Res. 2002 Jul 15;62(14):3914-9
references.pmid: 12124318
references.citation: Immunology. 2006 Oct;119(2):254-64
references.pmid: 17005005
references.citation: J Immunol. 2002 Nov 1;169(9):4897-904
references.pmid: 12391201
references.citation: J Immunol. 2000 Nov 1;165(9):4773-7
references.pmid: 11045997
references.citation: Eur J Immunol. 2008 Apr;38(4):915-7
references.pmid: 18395859
references.citation: J Exp Med. 2008 Sep 1;205(9):2125-38
references.pmid: 18725522
references.citation: Eur J Cancer. 1992;28(2-3):641-4
references.pmid: 1317202
references.citation: J Immunol. 2004 May 15;172(10):5986-93
references.pmid: 15128781
references.citation: J Immunol. 2001 Jun 15;166(12):7282-9
references.pmid: 11390478
references.citation: Cancer Res. 2005 Mar 15;65(6):2457-64
references.pmid: 15781662
references.citation: Gastroenterology. 1993 Dec;105(6):1846-56
references.pmid: 8253361
references.citation: J Exp Med. 2005 Nov 21;202(10):1375-86
references.pmid: 16287710
references.citation: J Exp Med. 2002 Jul 15;196(2):237-46
references.pmid: 12119348
references.citation: Cancer Res. 2006 Apr 15;66(8):4488-95
references.pmid: 16618776
references.citation: Am J Pathol. 1993 Aug;143(2):381-9
references.pmid: 8393616
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10398-403
references.pmid: 15235129
references.citation: Immunity. 2000 Feb;12(2):171-81
references.pmid: 10714683
references.citation: J Transl Med. 2007 Sep 14;5:43
references.pmid: 17868452
references.citation: Immunity. 2006 Sep;25(3):455-71
references.pmid: 16973386
references.citation: Immunol Rev. 2001 Aug;182:18-32
references.pmid: 11722621
references.citation: J Immunol. 2006 Nov 1;177(9):5852-60
references.pmid: 17056509
references.citation: Cancer Gene Ther. 2006 Dec;13(12):1052-60
references.pmid: 16826191
references.citation: J Exp Med. 2005 Apr 4;201(7):1061-7
references.pmid: 15809351
references.citation: J Exp Med. 2003 Dec 15;198(12):1875-86
references.pmid: 14676299
references.citation: J Immunol. 1995 Aug 1;155(3):1151-64
references.pmid: 7636184
references.citation: Curr Opin Immunol. 2007 Apr;19(2):217-23
references.pmid: 17306521
references.citation: Immunity. 2006 Sep;25(3):441-54
references.pmid: 16973387
references.citation: Nat Rev Immunol. 2003 Mar;3(3):253-7
references.pmid: 12658273
references.citation: Cancer Gene Ther. 1996 Jan-Feb;3(1):39-47
references.pmid: 8785710
references.citation: Nat Med. 2001 Oct;7(10):1118-22
references.pmid: 11590434
references.citation: Nature. 2007 Nov 22;450(7169):566-9
references.pmid: 18033300
references.citation: J Clin Invest. 2007 May;117(5):1167-74
references.pmid: 17476346
references.citation: Immunity. 2005 Mar;22(3):329-41
references.pmid: 15780990