title: Tumor-associated macrophages recruit CCR6+ regulatory T cells and promote the development of colorectal cancer via enhancing CCL20 production in mice.
abstract: BACKGROUND
  Tumor-associated macrophages (TAMs) remodel the colorectal cancer (CRC) microenvironment. Yet, findings on the role of TAMs in CRC seem to be contradictory compared with other cancers. FoxP3(+) regulatory T (Treg)-cells dominantly infiltrate CRC. However, the underlying molecular mechanism in which TAMs may contribute to the trafficking of Treg-cells to the tumor mass remains unknown.
  
  
  RESULTS
  CRC was either induced by N-methyl-N-nitrosourea (MNU) and H. pylori or established by subcutaneous injection of mouse colorectal tumor cell line (CMT93) in mice. CMT93 cells were co-cultured with primary macrophages in a transwell apparatus. Recruitment of FoxP3 green fluorescence protein positive (FoxP3(GFP+)) Treg-cells was assessed using the IVIS Imaging System or immunofluorescence staining. A role for macrophages in trafficking of Treg-cells and in the development of CRC was investigated in CD11b diphtheria toxin receptor (CD11b-DTR) transgenic C57BL/6J mice in which macrophages can be selectively depleted. Treg-cells remarkably infiltrated solid tumor, and predominantly expressed the homing chemokine receptor (CCR) 6 in the induced CRC model. Both CMT93 cancer cells and macrophages produced a large amount of CCL20, the sole ligand of CCR6 in vitro and in vivo. Injection of recombinant mouse CCL20 into tumor sites promoted its development with a marked recruitment of Treg-cells in the graft CRC model. Conditional macrophage ablation decreased CCL20 levels, blocked Treg-cell recruitment and inhibited tumor growth in CD11b-DTR mice grafted with CMT93.
  
  
  CONCLUSIONS
  TAMs recruit CCR6(+) Treg-cells to tumor mass and promote its development via enhancing the production of CCL20 in a CRC mouse model.
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Jinlin
authors.initials: J
authors.lastname: Liu
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Ke
authors.forename: Qibin
authors.initials: Q
authors.lastname: Leng
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Jinfei
authors.initials: J
authors.lastname: Chen
authors.forename: Honglin
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis; D054418:Chemokine CCL20 / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D049452:Green Fluorescent Proteins / Q000378:metabolism; D016480:Helicobacter pylori / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008770:Methylnitrosourea / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence / Q000379:methods; D054399:Receptors, CCR6 / Q000096:biosynthesis*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*
chemical_list: C493447:CCL20 protein, mouse; C498126:CCR6 protein, mouse; D039481:CD11b Antigen; D054418:Chemokine CCL20; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D054399:Receptors, CCR6; D049452:Green Fluorescent Proteins; D008770:Methylnitrosourea