title: Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient immunogenic signalling.
abstract: Clinical oncology heavily relies on the use of radiotherapy, which often leads to merely transient responses that are followed by local or distant relapse. The molecular mechanisms explaining radioresistance are largely elusive. Here, we identified a dual role of autophagy in the response of cancer cells to ionizing radiation. On one hand, we observed that the depletion of essential autophagy-relevant gene products, such as ATG5 and Beclin 1, increased the sensitivity of human or mouse cancer cell lines to irradiation, both in vitro (where autophagy inhibition increased radiation-induced cell death and decreased clonogenic survival) and in vivo, after transplantation of the cell lines into immunodeficient mice (where autophagy inhibition potentiated the tumour growth-inhibitory effect of radiotherapy). On the other hand, when tumour proficient or deficient for autophagy were implanted in immunocompetent mice, it turned out that defective autophagy reduced the efficacy of radiotherapy. Indeed, radiotherapy elicited an anti-cancer immune response that was dependent on autophagy-induced ATP release from stressed or dying tumour cells and was characterized by dense lymphocyte infiltration of the tumour bed. Intratumoural injection of an ecto-ATPase inhibitor restored the immune infiltration of autophagy-deficient tumours post radiotherapy and improved the growth-inhibitory effect of ionizing irradiation. Altogether, our results reveal that beyond its cytoprotective function, autophagy confers immunogenic properties to tumours, hence amplifying the efficacy of radiotherapy in an immunocompetent context. This has far-reaching implications for the development of pharmacological radiosensitizers.
authors.affiliation: 1] INSERM U1030, Radiothérapie moléculaire SIRIC SOCRATES, LABEX LERMIT & DHU TORINO, Institut Gustave Roussy, Villejuif, France [2] Gustave Roussy Cancer Campus, Villejuif, France [3] SIRIC SOCRATES, LABEX LERMIT & DHU TORINO, Université Paris Sud-Paris 11, Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Ko
authors.forename: A
authors.initials: A
authors.lastname: Kanehisa
authors.forename: I
authors.initials: I
authors.lastname: Martins
authors.forename: L
authors.initials: L
authors.lastname: Senovilla
authors.forename: C
authors.initials: C
authors.lastname: Chargari
authors.forename: D
authors.initials: D
authors.lastname: Dugue
authors.forename: G
authors.initials: G
authors.lastname: Mariño
authors.forename: O
authors.initials: O
authors.lastname: Kepp
authors.forename: M
authors.initials: M
authors.lastname: Michaud
authors.forename: J-L
authors.initials: JL
authors.lastname: Perfettini
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
authors.forename: E
authors.initials: E
authors.lastname: Deutsch
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000528:radiation effects*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D005720:Gamma Rays; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: C502778:ATG5 protein, human; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering
references.citation: Radiat Res. 2010 Mar;173(3):298-309
references.pmid: 20199215
references.citation: Science. 2000 Dec 1;290(5497):1717-21
references.pmid: 11099404
references.citation: Dis Esophagus. 2011 Aug;24(6):437-43
references.pmid: 21166739
references.citation: Cancer Lett. 2007 Oct 28;256(2):137-65
references.pmid: 17629396
references.citation: Int J Cancer. 2009 Aug 1;125(3):717-22
references.pmid: 19431142
references.citation: Int J Oncol. 2005 May;26(5):1401-10
references.pmid: 15809734
references.citation: Cell. 2009 Jun 12;137(6):1062-75
references.pmid: 19524509
references.citation: J Cell Biol. 2010 Jun 14;189(6):925-35
references.pmid: 20548099
references.citation: Curr Biol. 1999 Sep 9;9(17):967-70
references.pmid: 10508592
references.citation: Cell Death Differ. 2007 Oct;14(10):1848-50
references.pmid: 17657249
references.citation: Clin Cancer Res. 2009 Sep 1;15(17):5308-16
references.pmid: 19706824
references.citation: Tumour Biol. 2010 Aug;31(4):363-72
references.pmid: 20490962
references.citation: Cancer J Sci Am. 1996 Mar-Apr;2(2):114-21
references.pmid: 9166509
references.citation: Nat Rev Immunol. 2008 Jan;8(1):59-73
references.pmid: 18097448
references.citation: Nat Rev Cancer. 2003 Feb;3(2):117-29
references.pmid: 12563311
references.citation: Mol Cell. 2011 Apr 8;42(1):1-3
references.pmid: 21474062
references.citation: Science. 2010 Dec 3;330(6009):1344-8
references.pmid: 21127245
references.citation: Antioxid Redox Signal. 2014 Mar 1;20(7):1098-116
references.pmid: 23394620
references.citation: Surgery. 2009 Dec;146(6):1208-14
references.pmid: 19958950
references.citation: Science. 2011 Dec 16;334(6062):1573-7
references.pmid: 22174255
references.citation: Cell Death Differ. 2005 Nov;12 Suppl 2:1535-41
references.pmid: 16247501
references.citation: Cancer Res. 2008 Mar 1;68(5):1485-94
references.pmid: 18316613
references.citation: J Biol Chem. 2000 Jan 14;275(2):992-8
references.pmid: 10625637
references.citation: J Clin Invest. 2003 Dec;112(12):1809-20
references.pmid: 14638851
references.citation: Cell Death Differ. 2012 Jan;19(1):107-20
references.pmid: 21760595
references.citation: Cell. 2011 Nov 11;147(4):728-41
references.pmid: 22078875
references.citation: Genes Dev. 2010 Dec 1;24(23):2592-602
references.pmid: 21123646
references.citation: Autophagy. 2011 Mar;7(3):297-300
references.pmid: 21252623
references.citation: Radiat Oncol. 2012 Dec 17;7:213
references.pmid: 23244773
references.citation: Cancer Res. 2001 Jan 15;61(2):439-44
references.pmid: 11212227
references.citation: J Biol Chem. 2007 Jun 22;282(25):18573-18583
references.pmid: 17442669
references.citation: Radiat Res. 2011 Nov;176(5):587-602
references.pmid: 21823972
references.citation: Immunol Rev. 2007 Dec;220:22-34
references.pmid: 17979837
references.citation: Dev Cell. 2003 Oct;5(4):539-45
references.pmid: 14536056
references.citation: J Biol Chem. 2010 Mar 5;285(10):7176-86
references.pmid: 19858205
references.citation: Nat Med. 2007 Sep;13(9):1050-9
references.pmid: 17704786
references.citation: Oncotarget. 2011 Dec;2(12):1302-6
references.pmid: 22185891
references.citation: Lancet. 2008 Mar 1;371(9614):771-83
references.pmid: 18275997
references.citation: Nature. 2009 Sep 10;461(7261):282-6
references.pmid: 19741708
references.citation: Nat Cell Biol. 2010 Sep;12(9):814-22
references.pmid: 20811353
references.citation: J Natl Cancer Inst. 1979 Nov;63(5):1229-35
references.pmid: 291749
references.citation: Clin Cancer Res. 2009 Oct 1;15(19):6096-105
references.pmid: 19773376
references.citation: Nat Rev Mol Cell Biol. 2001 Mar;2(3):211-6
references.pmid: 11265251