title: Tumour microenvironment of both early- and late-stage colorectal cancer is equally immunosuppressive.
abstract: BACKGROUND
  Tumour microenvironment (TME) of advanced colorectal cancer (CRC) suppresses dendritic cell (DC) maturation. Here, our aim was to determine how the microenvironment of early-stage tumours influences DCs.
  
  
  METHODS
  Tumour-conditioned media (TCM) was generated by culturing explant tumour tissue in vitro (n=50). Monocyte-derived DCs (MDDCs) of healthy donors or cancer patients were pretreated with TCM and stimulated with lipopolysaccharide (LPS). DC maturation was assessed by flow cytometry and cytokine production measured by ELISA.
  
  
  RESULTS
  TCM from both early- and late-staged tumours abrogated LPS-induction of IL-12p70 secretion, while increasing IL-10. The profile of inflammatory mediators in TCM was similar across stages, and all increased pSTAT3 expression by DCs.CRC patient DCs (n=31) secreted low levels of IL-12p70 and failed to upregulate expression of maturation markers in response to LPS. Furthermore, in vitro culture of autologous DCs with TCM did not change the hypo-responsiveness of patient DCs.
  
  
  CONCLUSIONS
  Our data demonstrates that the TME of all stages of CRC contains inflammatory mediators capable of suppressing local DCs. MDDCs obtained from CRC patients are hyporesponsive to stimuli such as LPS. Measures to reverse the negative influence of the TME on DCs will optimise cancer vaccines in both early- and late-stage CRC.
authors: 1] Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland [2] School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors: A
authors: A
authors: O'Toole
authors: 1] Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland [2] Department of Surgery, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin 8, Ireland.
authors: A J
authors: AJ
authors: Michielsen
authors: Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland.
authors: B
authors: B
authors: Nolan
authors: Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland.
authors: M
authors: M
authors: Tosetto
authors: 1] Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland [2] School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors: K
authors: K
authors: Sheahan
authors: 1] Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland [2] School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors: H E
authors: HE
authors: Mulcahy
authors: 1] Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland [2] School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors: D C
authors: DC
authors: Winter
authors: 1] Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland [2] School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors: J M
authors: JM
authors: Hyland
authors: 1] Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland [2] School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors: P R
authors: PR
authors: O'Connell
authors: 1] Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland [2] School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors: D
authors: D
authors: Fennelly
authors: 1] Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland [2] School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors: D
authors: D
authors: O'Donoghue
authors: Department of Surgery, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin 8, Ireland.
authors: J
authors: J
authors: O'Sullivan
authors: 1] Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland [2] School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors: G A
authors: GA
authors: Doherty
authors: 1] Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland [2] School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.
authors: E J
authors: EJ
authors: Ryan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; D018664:Interleukin-12