title: The effects of CCR5 inhibition on regulatory T-cell recruitment to colorectal cancer.
abstract: BACKGROUND
  Regulatory T cells (Treg) are enriched in human colorectal cancer (CRC) where they suppress anti-tumour immunity. The chemokine receptor CCR5 has been implicated in the recruitment of Treg from blood into CRC and tumour growth is delayed in CCR5-/- mice, associated with reduced tumour Treg infiltration.
  
  
  METHODS
  Tissue and blood samples were obtained from patients undergoing resection of CRC. Tumour-infiltrating lymphocytes were phenotyped for chemokine receptors using flow cytometry. The presence of tissue chemokines was assessed. Standard chemotaxis and suppression assays were performed and the effects of CCR5 blockade were tested in murine tumour models.
  
  
  RESULTS
  Functional CCR5 was highly expressed by human CRC infiltrating Treg and CCR5(high) Treg were more suppressive than their CCR5(low) Treg counterparts. Human CRC-Treg were more proliferative and activated than other T cells suggesting that local proliferation could provide an alternative explanation for the observed tumour Treg enrichment. Pharmacological inhibition of CCR5 failed to reduce tumour Treg infiltration in murine tumour models although it did result in delayed tumour growth.
  
  
  CONCLUSIONS
  CCR5 inhibition does not mediate anti-tumour effects as a consequence of inhibiting Treg recruitment. Other mechanisms must be found to explain this effect. This has important implications for anti-CCR5 therapy in CRC.
authors.affiliation: Centre for Liver Research & NIHR Birmingham Biomedical Research Unit, Level 5 Institute for Biomedical Research, University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
authors.forename: S T
authors.initials: ST
authors.lastname: Ward
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU), University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
authors.forename: K K
authors.initials: KK
authors.lastname: Li
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU), University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
authors.forename: E
authors.initials: E
authors.lastname: Hepburn
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU), University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Weston
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU), University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Curbishley
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU), University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
authors.forename: G M
authors.initials: GM
authors.lastname: Reynolds
authors.affiliation: Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Birmingham B15 2WW, UK.
authors.forename: R K
authors.initials: RK
authors.lastname: Hejmadi
authors.affiliation: Institute for Biomedical Research, University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
authors.forename: R
authors.initials: R
authors.lastname: Bicknell
authors.affiliation: Snyder Institute, University of Calgary, Alberta T2N 4N1, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Eksteen
authors.affiliation: Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Birmingham B15 2WW, UK.
authors.forename: T
authors.initials: T
authors.lastname: Ismail
authors.affiliation: Institute for Biomedical Research, University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
authors.forename: A
authors.initials: A
authors.lastname: Rot
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU), University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
authors.forename: D H
authors.initials: DH
authors.lastname: Adams
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054407:Chemokine CCL4 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000276:immunology*; D003510:Cyclohexanes / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D000077592:Maraviroc; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D019713:Receptors, CCR5 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D065100:CCR5 Receptor Antagonists; C000592874:CCR5 protein, mouse; D054407:Chemokine CCL4; D003510:Cyclohexanes; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc