title: T-helper-1-cell cytokines drive cancer into senescence.
abstract: Cancer control by adaptive immunity involves a number of defined death and clearance mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-γ (IFN-γ) requires additional undefined mechanisms that arrest cancer cell proliferation. Here we show that the combined action of the T-helper-1-cell cytokines IFN-γ and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from oncogene-induced senescence, we used a mouse model in which the Simian virus 40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumours by attenuating p53- and Rb-mediated cell cycle control. When combined, IFN-γ and TNF drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16INK4a (also known as CDKN2A), and downstream Rb hypophosphorylation at serine 795. This cytokine-induced senescence strictly requires STAT1 and TNFR1 (also known as TNFRSF1A) signalling in addition to p16INK4a. In vivo, Tag-specific T-helper 1 cells permanently arrest Tag-expressing cancers by inducing IFN-γ- and TNFR1-dependent senescence. Conversely, Tnfr1(-/-)Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in TNFR1-expressing hosts. Finally, as IFN-γ and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.
authors: Department of Dermatology, Eberhard Karls University, Liebermeister Strasse 25, 72076 Tübingen, Germany.
authors: Heidi
authors: H
authors: Braumüller
authors: Thomas
authors: T
authors: Wieder
authors: Ellen
authors: E
authors: Brenner
authors: Sonja
authors: S
authors: Aßmann
authors: Matthias
authors: M
authors: Hahn
authors: Mohammed
authors: M
authors: Alkhaled
authors: Karin
authors: K
authors: Schilbach
authors: Frank
authors: F
authors: Essmann
authors: Manfred
authors: M
authors: Kneilling
authors: Christoph
authors: C
authors: Griessinger
authors: Felicia
authors: F
authors: Ranta
authors: Susanne
authors: S
authors: Ullrich
authors: Ralph
authors: R
authors: Mocikat
authors: Kilian
authors: K
authors: Braungart
authors: Tarun
authors: T
authors: Mehra
authors: Birgit
authors: B
authors: Fehrenbacher
authors: Julia
authors: J
authors: Berdel
authors: Heike
authors: H
authors: Niessner
authors: Friedegund
authors: F
authors: Meier
authors: Maries
authors: M
authors: van den Broek
authors: Hans-Ulrich
authors: HU
authors: Häring
authors: Rupert
authors: R
authors: Handgretinger
authors: Leticia
authors: L
authors: Quintanilla-Martinez
authors: Falko
authors: F
authors: Fend
authors: Marina
authors: M
authors: Pesic
authors: Jürgen
authors: J
authors: Bauer
authors: Lars
authors: L
authors: Zender
authors: Martin
authors: M
authors: Schaller
authors: Klaus
authors: K
authors: Schulze-Osthoff
authors: Martin
authors: M
authors: Röcken
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000276:immunology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000276:immunology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology*; D009857:Oncogenes / Q000235:genetics; D010768:Phosphoserine / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000952:Antigens, Polyomavirus Transforming; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016207:Cytokines; D047888:Receptors, Tumor Necrosis Factor, Type I; D016160:Retinoblastoma Protein; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D010768:Phosphoserine; D007371:Interferon-gamma
references: J Clin Invest. 2010 Jun;120(6):1800-3
references: 20501952
references: Cell. 2011 Mar 4;144(5):646-74
references: 21376230
references: J Natl Cancer Inst. 1991 Jun 5;83(11):757-66
references: 2041050
references: Blood. 2009 Aug 20;114(8):1696-706
references: 19546478
references: N Engl J Med. 2008 Jun 19;358(25):2704-15
references: 18565863
references: Nat Genet. 2005 Nov;37(11):1289-95
references: 16200064
references: Cell. 2008 Jun 13;133(6):1019-31
references: 18555778
references: Immunity. 1995 Jun;2(6):573-85
references: 7796292
references: Immunity. 2003 Oct;19(4):561-9
references: 14563320
references: Blood. 2009 Apr 9;113(15):3494-502
references: 19188665
references: Science. 1999 Apr 30;284(5415):808-12
references: 10221914
references: Science. 2011 Mar 25;331(6024):1565-70
references: 21436444
references: Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):9010-5
references: 19451644
references: Nature. 2007 Dec 6;450(7171):903-7
references: 18026089
references: Cancer Res. 2009 Apr 1;69(7):2956-65
references: 19339270
references: N Engl J Med. 2010 Aug 19;363(8):711-23
references: 20525992
references: Nature. 2011 Nov 09;479(7374):547-51
references: 22080947
references: Nat Rev Immunol. 2007 Feb;7(2):118-30
references: 17259968
references: N Engl J Med. 2009 Nov 5;361(19):1838-47
references: 19890126
references: J Exp Med. 2000 Nov 20;192(10):1441-52
references: 11085746
references: N Engl J Med. 2011 Jun 2;364(22):2119-27
references: 21631324
references: Toxicol Pathol. 2007 Apr;35(3):366-75
references: 17455084
references: Oncogene. 2012 Mar 29;31(13):1723-32
references: 21841823
references: Nat Rev Mol Cell Biol. 2007 Sep;8(9):729-40
references: 17667954
references: Cell. 2008 Jun 13;133(6):1006-18
references: 18555777
references: J Exp Med. 1998 Dec 21;188(12):2357-68
references: 9858522
references: Nat Rev Cancer. 2010 Jan;10(1):51-7
references: 20029423
references: Cell. 1993 May 7;73(3):457-67
references: 8387893
references: J Exp Med. 1996 Nov 1;184(5):1781-90
references: 8920866
references: Nature. 2005 Aug 4;436(7051):660-5
references: 16079837
references: Oncogene. 2005 Oct 6;24(44):6597-604
references: 16007165
references: Nat Rev Cancer. 2011 Jun 24;11(7):503-11
references: 21701512
references: Nature. 1985 May 9-15;315(6015):115-22
references: 2986015
references: Science. 2006 Oct 6;314(5796):126-9
references: 16946036
references: Cancer Res. 2001 Nov 15;61(22):8298-305
references: 11719463
references: Cancer Cell. 2008 Jun;13(6):507-18
references: 18538734
references: Nature. 2007 Feb 8;445(7128):656-60
references: 17251933
references: Diabetes. 2010 Jan;59(1):119-27
references: 19826167
references: J Clin Invest. 2008 Apr;118(4):1398-404
references: 18317595
references: Genes Dev. 2005 Sep 1;19(17):1986-99
references: 16107615
references: Nature. 2005 Sep 1;437(7055):141-6
references: 16136144
references: Cancer Cell. 2010 Nov 16;18(5):485-98
references: 21035406
references: N Engl J Med. 2008 Jun 19;358(25):2698-703
references: 18565862