title: Myeloid-derived suppressor cells have a central role in attenuated Listeria monocytogenes-based immunotherapy against metastatic breast cancer in young and old mice.
abstract: BACKGROUND
  Myeloid-derived suppressor cells (MDSCs) are present in large numbers in blood of mice and humans with cancer, and they strongly inhibit T-cell and natural killer (NK) cell responses, at young and old age. We found that a highly attenuated bacterium Listeria monocytogenes (Listeria(at))-infected MDSC and altered the immune-suppressing function of MDSC.
  
  
  METHODS
  Young (3 months) and old (18 months) BALB/cByJ mice with metastatic breast cancer (4T1 model) were immunised with Listeria(at) semi-therapeutically (once before and twice after tumour development), and analysed for growth of metastases and primary tumour, in relation to MDSC-, CD8 T-cell and NK cell responses.
  
  
  RESULTS
  We found that Listeria(at)-infected MDSC, which delivered Listeria(at) predominantly to the microenvironment of metastases and primary tumours, where they spread from MDSC into tumour cells (infected tumour cells will ultimately become a target for Listeria-activated immune cells). Immunotherapy with Listeria(at) significantly reduced the population of MDSC in blood and primary tumours, and converted a remaining subpopulation of MDSC into an immune-stimulating phenotype producing IL-12, in correlation with significantly improved T-cell and NK cell responses to Listeria(at) at both ages. This was accompanied with a dramatic reduction in the number of metastases and tumour growth at young and old age.
  
  
  CONCLUSIONS
  Although preclinical studies show that immunotherapy is less effective at old than at young age, our study demonstrates that Listeria(at)-based immunotherapy can be equally effective against metastatic breast cancer at both young and old age by targeting MDSC.
authors: Albert Einstein College of Medicine, Department of Microbiology and Immunology, 1300 Morris Park Avenue, Forchheimer Building, Room F407, Bronx, NY 10461, USA.
authors: D
authors: D
authors: Chandra
authors: A
authors: A
authors: Jahangir
authors: W
authors: W
authors: Quispe-Tintaya
authors: M H
authors: MH
authors: Einstein
authors: C
authors: C
authors: Gravekamp
mesh_terms: D000367:Age Factors; D000818:Animals; D005260:Female; D007167:Immunotherapy / Q000379:methods; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology / Q000382:microbiology; D008089:Listeria monocytogenes / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000382:microbiology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000382:microbiology
chemical_list: D018664:Interleukin-12
references: Curr Treat Options Oncol. 2011 Sep;12(3):276-85
references: 21656152
references: Aging Cell. 2012 Dec;11(6):968-77
references: 22862959
references: Cancer Res. 2009 Jul 1;69(13):5514-21
references: 19549903
references: Immunology. 2003 Jul;109(3):407-14
references: 12807487
references: Mech Ageing Dev. 2007 Nov-Dec;128(11-12):672-80
references: 18036633
references: Science. 1993 Apr 23;260(5107):547-9
references: 8097338
references: Cancer Immunol Immunother. 2009 Jan;58(1):49-59
references: 18446337
references: Gene Ther. 2000 Apr;7(7):624-32
references: 10819579
references: CA Cancer J Clin. 2005 Jan-Feb;55(1):10-30
references: 15661684
references: J Immunol. 2002 Dec 15;169(12):6842-9
references: 12471116
references: Cancer Res. 1992 Mar 15;52(6):1399-405
references: 1540948
references: Cancer Res. 2009 Jul 15;69(14):5860-6
references: 19584282
references: J Clin Oncol. 2009 Jun 10;27(17):2758-65
references: 19403886
references: Br J Cancer. 2008 Sep 2;99(5):741-9
references: 18728665
references: Curr Opin Immunol. 2011 Aug;23(4):555-60
references: 21763118
references: J Immunol. 2006 Dec 15;177(12):8348-55
references: 17142731
references: Blood. 2008 Apr 15;111(8):4233-44
references: 18272812
references: J Immunol. 2008 Oct 15;181(8):5791-802
references: 18832739
references: Genomics. 1995 Jul 1;28(1):74-83
references: 7590750
references: Cell Microbiol. 2007 Jun;9(6):1445-54
references: 17244189
references: J Cell Biol. 2002 Aug 5;158(3):409-14
references: 12163465
references: Cancer Immunol Immunother. 2012 Mar;61(3):363-71
references: 21922332
references: Nat Rev Immunol. 2009 Mar;9(3):162-74
references: 19197294
references: Blood. 2011 May 19;117(20):5381-90
references: 21450901
references: Vaccine. 2003 Feb 14;21(9-10):843-8
references: 12547592
references: J Exp Med. 1987 Dec 1;166(6):1685-701
references: 2445894
references: Aging Cell. 2012 Oct;11(5):732-40
references: 22607653
references: J Immunol. 2005 Sep 15;175(6):3663-73
references: 16148111
references: Cancer Biol Ther. 2010 Feb;9(4):257-65
references: 20139702
references: Cancer Cell. 2012 Jun 12;21(6):836-47
references: 22698407
references: Clin Cancer Res. 2009 Feb 1;15(3):924-32
references: 19188163
references: Clin Microbiol Infect. 2012 Oct;18 Suppl 5:100-8
references: 22862783
references: J Immunol. 2009 Apr 15;182(8):4499-506
references: 19342621
references: Vaccine. 2009 Jun 19;27(30):3975-83
references: 19389451
references: Microbes Infect. 2007 Aug;9(10):1208-15
references: 17719259
references: J Immunol. 2004 Oct 1;173(7):4510-5
references: 15383582
references: J Immunol. 2001 Dec 1;167(11):6471-9
references: 11714814
references: Cancer Res. 1999 Oct 15;59(20):5264-9
references: 10537307
references: Mech Ageing Dev. 1992 Mar 15;63(1):57-68
references: 1376382
references: Br J Cancer. 2009 Oct 20;101(8):1329-37
references: 19826426
references: Immunol Today. 1996 Jun;17(6):267-72
references: 8962629
references: Science. 1996 Jul 5;273(5271):70-4
references: 8658199
references: Lab Invest. 1972 Jun;26(6):694-700
references: 4624183