title: Lymphocyte depletion and repopulation after chemotherapy for primary breast cancer.
abstract: BACKGROUND
  Approximately 30 % of breast cancer patients receive chemotherapy, yet little is known about influences of current regimens on circulating lymphocyte levels and phenotypes. Similarly, clinico-pathological factors that modify these influences, and implications for future immune health remain mainly unexplored.
  
  
  METHODS
  We used flow-cytometry to assess circulating lymphocyte levels and phenotypes in 88 primary breast cancer patients before chemotherapy and at time-points from 2 weeks to 9 months after chemotherapy completion. We examined circulating titres of antibodies against pneumococcal and tetanus antigens using ELISAs.
  
  
  RESULTS
  Levels of B, T and NK cells were significantly reduced 2 weeks after chemotherapy (p < 0.001). B cells demonstrated particularly dramatic depletion, falling to 5.4 % of pre-chemotherapy levels. Levels of all cells recovered to some extent, although B and CD4(+) T cells remained significantly depleted even 9 months post-chemotherapy (p < 0.001). Phenotypes of repopulating B and CD4(+) T cells were significantly different from, and showed no sign of returning to pre-chemotherapy profiles. Repopulating B cells were highly depleted in memory cells, with proportions of memory cells falling from 38 % to 10 % (p < 0.001). Conversely, repopulating CD4(+) T cells were enriched in memory cells, which increased from 63 % to 75 % (p < 0.001). Differences in chemotherapy regimen and patient smoking were associated with significant differences in depletion extent or repopulation dynamics. Titres of anti-pneumococcal and anti-tetanus antibodies were both significantly reduced post-chemotherapy and did not recover during the study (p < 0.001).
  
  
  CONCLUSIONS
  Breast cancer chemotherapy is associated with long-term changes in immune parameters that should be considered during clinical management.
authors.affiliation: School of Medicine, University of Leeds, Leeds, UK. docrash12@yahoo.co.uk.|Department of Breast Surgery, Leeds Teaching Hospitals NHS Trust, Leeds, UK. docrash12@yahoo.co.uk.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Verma
authors.affiliation: Department of Transplant Immunology, Leeds Teaching Hospitals NHS Trust, Leeds, UK. ruthfoster5@nhs.net.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Foster
authors.affiliation: School of Medicine, University of Leeds, Leeds, UK. kieran.horgan@nhs.net.|Department of Breast Surgery, Leeds Teaching Hospitals NHS Trust, Leeds, UK. kieran.horgan@nhs.net.
authors.forename: Kieran
authors.initials: K
authors.lastname: Horgan
authors.affiliation: Department of Transplant Immunology, Leeds Teaching Hospitals NHS Trust, Leeds, UK. katherine.mounsey@nhs.net.
authors.forename: Katherine
authors.initials: K
authors.lastname: Mounsey
authors.affiliation: Clinical Immunology Laboratories, Leeds Teaching Hospitals NHS Trust, Leeds, UK. helen.nixon5@nhs.net.
authors.forename: Helen
authors.initials: H
authors.lastname: Nixon
authors.affiliation: Department of Transplant Immunology, Leeds Teaching Hospitals NHS Trust, Leeds, UK. n.smalle@rbht.nhs.uk.
authors.forename: Natuley
authors.initials: N
authors.lastname: Smalle
authors.affiliation: School of Medicine, University of Leeds, Leeds, UK. t.hughes@leeds.ac.uk.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hughes
authors.affiliation: School of Medicine, University of Leeds, Leeds, UK. clivecarter@nhs.net.|Department of Transplant Immunology, Leeds Teaching Hospitals NHS Trust, Leeds, UK. clivecarter@nhs.net.
authors.forename: Clive R D
authors.initials: CR
authors.lastname: Carter
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology* / Q000302:isolation & purification; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008212:Lymphocyte Depletion; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D013296:Streptococcus pneumoniae / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013742:Tetanus / Q000276:immunology / Q000382:microbiology
chemical_list: D000906:Antibodies; D015703:Antigens, CD
references.citation: Int J Cancer. 2015 Mar 1;136(5):E359-86
references.pmid: 25220842
references.citation: Br J Cancer. 2007 Jul 2;97(1):105-11
references.pmid: 17551492
references.citation: Acta Radiol Oncol. 1982;21(4):217-24
references.pmid: 6293264
references.citation: Ann Intern Med. 2003 Jan 21;138(2):90-7
references.pmid: 12529090
references.citation: Cell Mol Life Sci. 2015 Nov;72(21):4049-62
references.pmid: 26174234
references.citation: Biol Blood Marrow Transplant. 2009 Jul;15(7):795-803
references.pmid: 19539210
references.citation: Transplantation. 2012 Apr 27;93(8):813-21
references.pmid: 22343334
references.citation: Nat Med. 2015 Oct;21(10):1128-38
references.pmid: 26444637
references.citation: Cancer. 2006 May 15;106(10):2258-66
references.pmid: 16575919
references.citation: Cancer. 2000 Sep 15;89(6):1380-6
references.pmid: 11002234
references.citation: Br J Haematol. 2001 Dec;115(3):630-41
references.pmid: 11736948
references.citation: J Chemother. 2007 Dec;19(6):716-23
references.pmid: 18230556
references.citation: Cancer Immunol Immunother. 2009 Jan;58(1):111-20
references.pmid: 18488220
references.citation: Inhal Toxicol. 2010 Aug;22(9):785-96
references.pmid: 20482464
references.citation: Br J Haematol. 2002 May;117(2):444-50
references.pmid: 11972532
references.citation: Breast Cancer Res Treat. 2004 Sep;87(1):75-86
references.pmid: 15377853
references.citation: Lancet Oncol. 2014 Feb;15(2):e58-68
references.pmid: 24480556
references.citation: Blood. 2013 Feb 21;121(8):e50-6
references.pmid: 23287867
references.citation: Breast Care (Basel). 2014 Apr;9(4):239-45
references.pmid: 25404882
references.citation: J Natl Cancer Inst. 2015 Jan;107(1):335
references.pmid: 25432407
references.citation: Aging Cell. 2009 Feb;8(1):18-25
references.pmid: 18986373
references.citation: J Med Virol. 2003 Aug;70(4):553-61
references.pmid: 12794717
references.citation: J Clin Oncol. 2006 Dec 20;24(36):5664-71
references.pmid: 17116941
references.citation: Cytokine Growth Factor Rev. 2014 Aug;25(4):355-67
references.pmid: 25131807
references.citation: Immunol Cell Biol. 2010 Mar-Apr;88(3):321-7
references.pmid: 20065992
references.citation: Blood. 1997 Nov 1;90(9):3789-98
references.pmid: 9345067
references.citation: BMC Med. 2015;13:195
references.pmid: 26278220
references.citation: Neurology. 2013 Sep 3;81(10):872-6
references.pmid: 23925762
references.citation: Clin Chem Lab Med. 2015 Jan;53(1):57-64
references.pmid: 25029083
references.citation: Tumori. 2000 Sep-Oct;86(5):403-7
references.pmid: 11130570
references.citation: Pediatrics. 2002 Jun;109(6):e91
references.pmid: 12042585
references.citation: Immunology. 2002 May;106(1):27-37
references.pmid: 11972629
references.citation: Cancer. 2004 Aug 1;101(3):635-41
references.pmid: 15274078
references.citation: Am J Transplant. 2012 Apr;12(4):919-31
references.pmid: 22390816
references.citation: Breast J. 2015 Sep-Oct;21(5):508-13
references.pmid: 26132228
references.citation: Blood. 2011 Jan 13;117(2):530-41
references.pmid: 20962324
references.citation: Oncology. 2006;71(3-4):164-7
references.pmid: 17641534
references.citation: Blood. 1997 May 15;89(10):3700-7
references.pmid: 9160675
references.citation: J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):298-304
references.pmid: 22056965
references.citation: Blood. 2009 Jan 22;113(4):769-74
references.pmid: 18583570
references.citation: Lancet. 2005 May 14-20;365(9472):1687-717
references.pmid: 15894097
references.citation: Cancer. 1984 Jun 15;53(12):2619-27
references.pmid: 6609758
references.citation: Bone Marrow Transplant. 1993 Oct;12(4):387-98
references.pmid: 8275039
references.citation: Semin Neurol. 2013 Feb;33(1):66-73
references.pmid: 23709214
references.citation: Haematologica. 2013 Mar;98(3):325-33
references.pmid: 22929978