title: Tumour tissue microenvironment can inhibit dendritic cell maturation in colorectal cancer.
abstract: Inflammatory mediators in the tumour microenvironment promote tumour growth, vascular development and enable evasion of anti-tumour immune responses, by disabling infiltrating dendritic cells. However, the constituents of the tumour microenvironment that directly influence dendritic cell maturation and function are not well characterised. Our aim was to identify tumour-associated inflammatory mediators which influence the function of dendritic cells. Tumour conditioned media obtained from cultured colorectal tumour explant tissue contained high levels of the chemokines CCL2, CXCL1, CXCL5 in addition to VEGF. Pre-treatment of monocyte derived dendritic cells with this tumour conditioned media inhibited the up-regulation of CD86, CD83, CD54 and HLA-DR in response to LPS, enhancing IL-10 while reducing IL-12p70 secretion. We examined if specific individual components of the tumour conditioned media (CCL2, CXCL1, CXCL5) could modulate dendritic cell maturation or cytokine secretion in response to LPS. VEGF was also assessed as it has a suppressive effect on dendritic cell maturation. Pre-treatment of immature dendritic cells with VEGF inhibited LPS induced upregulation of CD80 and CD54, while CXCL1 inhibited HLA-DR. Interestingly, treatment of dendritic cells with CCL2, CXCL1, CXCL5 or VEGF significantly suppressed their ability to secrete IL-12p70 in response to LPS. In addition, dendritic cells treated with a combination of CXCL1 and VEGF secreted less IL-12p70 in response to LPS compared to pre-treatment with either cytokine alone. In conclusion, tumour conditioned media strongly influences dendritic cell maturation and function.
authors: Centre for Colorectal Disease, St. Vincent's University Hospital, Elm Park, Dublin, Ireland.
authors: Adriana J
authors: AJ
authors: Michielsen
authors: Andrew E
authors: AE
authors: Hogan
authors: Joseph
authors: J
authors: Marry
authors: Miriam
authors: M
authors: Tosetto
authors: Fionnuala
authors: F
authors: Cox
authors: John M
authors: JM
authors: Hyland
authors: Kieran D
authors: KD
authors: Sheahan
authors: Diarmuid P
authors: DP
authors: O'Donoghue
authors: Hugh E
authors: HE
authors: Mulcahy
authors: Elizabeth J
authors: EJ
authors: Ryan
authors: Jacintha N
authors: JN
authors: O'Sullivan
mesh_terms: D000368:Aged; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D054360:Chemokine CXCL1 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D054365:Chemokine CXCL5 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D046509:Tissue Culture Techniques; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D051940:B7-2 Antigen; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; D017077:Culture Media, Conditioned; D006684:HLA-DR Antigens; D007136:Immunoglobulins; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D042461:Vascular Endothelial Growth Factor A; D000097802:CD83 Antigen