title: Head and neck cancer relapse after chemoradiotherapy correlates with CD163+ macrophages in primary tumour and CD11b+ myeloid cells in recurrences.
abstract: BACKGROUND
  We investigated the prognostic role of tumour-associated macrophages (TAMs) in patients with head and neck squamous cell carcinoma (HNSCC) treated with definitive chemoradiotherapy (CRT).
  
  
  METHODS
  The expression of CD68+, CD163+ and CD11b+ cells was assessed using immunohistochemistry in n=106 pre-treatment tumour biopsy samples and was correlated with clinicopathological characteristics, including T-stage, N-stage, grading, tumour localisation, age and sex as well as local failure-free survival (LFFS), distant metastases-free survival (DMFS), progression-free (PFS), and overall survival (OS). Finally, TAMs expression and vessel density (CD31) were examined in n=12 available early local recurrence samples and compared with their matched primary tumours . The diagnostic images and radiotherapy plans of these 12 patients were also analysed. All local recurrences occurred in the high radiation dose region (⩾70 Gy).
  
  
  RESULTS
  With a median follow-up of 40 months, OS at 2 years was 60.5%. High CD163 expression in primary tumours was associated with decreased OS (P=0.010), PFS (P=0.033), LFFS (P=0.036) and DMFS (P=0.038) in multivariate analysis. CD163 demonstrated a strong prognostic value only in human papillomavirus (p16(INK4))-negative patients. Early local recurrence specimens demonstrated a significantly increased infiltration of CD11b+ myeloid cells (P=0.0097) but decreased CD31-positive vessel density (P=0.0004) compared with their matched primary samples.
  
  
  CONCLUSIONS
  Altogether, baseline CD163 expression predicts for an unfavourable clinical outcome in HNSCC after definitive CRT. Early local recurrences showed increased infiltration by CD11b+ cells. These data provide important insight on the role of TAMs in mediating response to CRT in patients with HNSCC.
authors.affiliation: Department of Radiation Therapy and Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Balermpas
authors.affiliation: Department of Radiation Therapy and Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Rödel
authors.affiliation: Senckenberg Institute of Pathology, Goethe University, Frankfurt, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Liberz
authors.affiliation: Department of Radiation Therapy and Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Oppermann
authors.affiliation: Department of Head and Neck Surgery, Goethe University, Frankfurt, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Wagenblast
authors.affiliation: Department of Maxillofacial Surgery, Goethe University, Frankfurt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Ghanaati
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University, Frankfurt, Germany.
authors.forename: P N
authors.initials: PN
authors.lastname: Harter
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University, Frankfurt, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Mittelbronn
authors.affiliation: Department of Radiation Therapy and Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Weiss
authors.affiliation: 1] Department of Radiation Therapy and Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany [2] German Cancer Consortium (DKTK), Partner Site Frankfurt and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Rödel
authors.affiliation: Department of Radiation Therapy and Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Fokas
mesh_terms: D015703:Antigens, CD / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000276:immunology*; D039481:CD11b Antigen / Q000276:immunology*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011878:Radiotherapy; D011956:Receptors, Cell Surface / Q000276:immunology*; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents; D039481:CD11b Antigen; D000098902:CD163 Antigen; C509295:ITGAM protein, human; D011956:Receptors, Cell Surface
references.citation: Cancer Cell. 2008 Mar;13(3):193-205
references.pmid: 18328424
references.citation: Cell Death Dis. 2012 Dec 06;3:e441
references.pmid: 23222511
references.citation: J Clin Oncol. 2009 Jul 10;27(20):3330-7
references.pmid: 19528371
references.citation: Cancer. 2004 Dec 15;101(12):2779-87
references.pmid: 15546137
references.citation: Cancers (Basel). 2011 Sep 28;3(4):3726-39
references.pmid: 24213108
references.citation: J Exp Med. 2001 Dec 3;194(11):1549-59
references.pmid: 11733570
references.citation: Cancer Immunol Immunother. 1994 Jan;38(1):31-7
references.pmid: 8299116
references.citation: J Clin Invest. 2010 Mar;120(3):694-705
references.pmid: 20179352
references.citation: Semin Radiat Oncol. 2013 Oct;23(4):281-7
references.pmid: 24012342
references.citation: Cancer Res. 2013 May 1;73(9):2782-94
references.pmid: 23418320
references.citation: Int J Cancer. 2012 Aug 1;131(3):E227-35
references.pmid: 22174092
references.citation: Urol Oncol. 2014 May;32(4):449-57
references.pmid: 24252833
references.citation: Cancer Cell. 2012 Apr 17;21(4):488-503
references.pmid: 22516258
references.citation: Cell. 2010 Apr 2;141(1):39-51
references.pmid: 20371344
references.citation: J Clin Invest. 2007 May;117(5):1130-6
references.pmid: 17476342
references.citation: Hypertension. 2014 Jun;63(6):1241-50
references.pmid: 24711518
references.citation: Proc Natl Acad Sci U S A. 2010 May 4;107(18):8363-8
references.pmid: 20404138
references.citation: Radiother Oncol. 2011 Oct;101(1):80-5
references.pmid: 21724288
references.citation: J Clin Invest. 2006 Aug;116(8):2132-2141
references.pmid: 16862213
references.citation: Nat Rev Immunol. 2009 Mar;9(3):162-74
references.pmid: 19197294
references.citation: J Clin Oncol. 2011 Nov 10;29(32):4294-301
references.pmid: 21969503
references.citation: Blood. 2012 Oct 18;120(16):3280-7
references.pmid: 22948049
references.citation: Cancer Cell. 2013 Mar 18;23(3):277-86
references.pmid: 23518347
references.citation: Clin Cancer Res. 2008 Mar 1;14(5):1423-30
references.pmid: 18316565
references.citation: Cancer Metastasis Rev. 2012 Dec;31(3-4):823-42
references.pmid: 22825313
references.citation: Cancer Discov. 2011 Jun;1(1):54-67
references.pmid: 22039576
references.citation: Neuropathol Appl Neurobiol. 2014 Feb;40(2):205-16
references.pmid: 24117486
references.citation: Nat Med. 2013 Oct;19(10):1264-72
references.pmid: 24056773
references.citation: Int J Radiat Oncol Biol Phys. 2011 Aug 1;80(5):1412-22
references.pmid: 20675073
references.citation: Nat Med. 2013 Jan;19(1):57-64
references.pmid: 23202296
references.citation: N Engl J Med. 2010 Jul 1;363(1):24-35
references.pmid: 20530316
references.citation: Lancet. 2008 May 17;371(9625):1695-709
references.pmid: 18486742
references.citation: Br J Cancer. 2014 Jan 21;110(2):501-9
references.pmid: 24129245
references.citation: Clin Cancer Res. 2009 Mar 1;15(5):1721-9
references.pmid: 19240176
references.citation: Oncol Rep. 2002 Nov-Dec;9(6):1219-23
references.pmid: 12375023
references.citation: J Pathol. 2012 Oct;228(2):170-80
references.pmid: 22262246
references.citation: Cancer Cell. 2004 May;5(5):429-41
references.pmid: 15144951
references.citation: J Clin Oncol. 2009 Apr 20;27(12):1992-8
references.pmid: 19289615
references.citation: Head Neck Oncol. 2013 Feb 27;5(3):24
references.pmid: 24723971
references.citation: J Oral Pathol Med. 2012 Jul;41(6):444-51
references.pmid: 22296275
references.citation: Int J Radiat Oncol Biol Phys. 2011 Jun 1;80(2):522-31
references.pmid: 20646862
references.citation: J Immunol Methods. 2012 Jan 31;375(1-2):196-206
references.pmid: 22075274
references.citation: BMC Cancer. 2012 Jul 23;12:306
references.pmid: 22824040
references.citation: Clin Cancer Res. 2012 Oct 1;18(19):5196-202
references.pmid: 22730447
references.citation: Am J Clin Pathol. 2004 Nov;122(5):794-801
references.pmid: 15491976
references.citation: J Clin Oncol. 2005 Feb 20;23(6):1125-35
references.pmid: 15718308
references.citation: Cancer Res. 2010 Jul 15;70(14):5679-85
references.pmid: 20631066
references.citation: N Engl J Med. 2010 Mar 11;362(10):875-85
references.pmid: 20220182
references.citation: Cancer Res. 2013 Mar 15;73(6):1733-41
references.pmid: 23288508
references.citation: Int J Radiat Oncol Biol Phys. 2006 Nov 15;66(4):1219-27
references.pmid: 17145537
references.citation: Radiat Res. 1990 Aug;123(2):232-6
references.pmid: 2389010